Phosphonium ion channel blockers and methods for use

ABSTRACT

The compounds, compositions, methods and kits of the invention are useful for the treatment of pain, itch, and neurogenic inflammation.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 62/931,407, filed on Nov. 6, 2019. The entire teachings of the above application are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to phosphonium compounds, pharmaceutical compositions, and methods useful as selective inhibitors of pain, cough, and itch sensing neurons (nociceptors, cough receptors and pruriceptors) and in the treatment of neurogenic inflammation.

BACKGROUND OF THE INVENTION

The invention features compounds, compositions and methods for the selective inhibition of sensory neurons (nociceptors, cough receptors and pruriceptors) and the treatment of neurogenic inflammation by targeting nociceptors with a small molecule drug, while minimizing effects on non-nociceptive neurons or other types of cells. According to the method of the invention, small, cationic drug molecules gain access to the intracellular compartment of sensory neurons via entry through large pore receptor/ion channels that are present in pain- cough- and itch-sensing neurons but to a lesser extent or not at all in other types of neurons or in other types of tissue.

Local anesthetics such as lidocaine and articaine act by inhibiting voltage-dependent sodium channels in neurons. These anesthetics block sodium channels and thereby the excitability of all neurons, not just pain-sensing neurons (nociceptors). Thus, while the goal of topical or regional anesthesia is to block transmission of signals in nociceptors to prevent pain, administration of local anesthetics also produces unwanted or deleterious effects such as general numbness from block of low threshold pressure and touch receptors, motor deficits and/or paralysis from block of motor axons and other complications from block of autonomic fibers. Local anesthetics are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing through the cell membrane. Charged derivatives of these compounds, which are not membrane-permeable, have no effect on neuronal sodium channels when applied to the external surface of the nerve membrane but can block sodium channels if somehow introduced inside the cell, for example, by diffusion from a micropipette used for whole-cell electrophysiological recording from isolated neurons. Pain-, cough-, and itch-sensing neurons differ from other types of neurons in expressing (in most cases) the TRPV1 receptor/channel, which is activated by painful heat or by capsaicin, the pungent ingredient in chili pepper. Other types of channels selectively expressed in various types of pain-sensing, cough-sensing and itch-sensing (pruriceptor) neurons include, but are not limited to, TRPV2-4, TRPA1, TRPM8, ASIC and P2X(2/3) channels. It is well established that some cationic small molecules such as QX-314 are able to enter a cell via passage through activated large pore channels such as TRPV1.

Neuropathic, inflammatory, and nociceptive pain differ in their etiology, pathophysiology, diagnosis, and treatment. Nociceptive pain occurs in response to the activation of a specific subset of high threshold peripheral sensory neurons, the nociceptors, by intense or noxious stimuli. It is generally acute, self-limiting and serves a protective biological function by acting as a warning of potential or on-going tissue damage. It is typically well-localized. Examples of nociceptive pain include, but are not limited to, traumatic or surgical pain, labor pain, sprains, bone fractures, burns, bumps, bruises, injections, dental procedures, skin biopsies, and obstructions.

Inflammatory pain is pain that occurs in the presence of tissue damage or inflammation including postoperative (i.e. pain associated with acute perioperative pain resulting from inflammation caused by tissue trauma (e.g., surgical incision, dissection, burns) or direct nerve injury (e.g., nerve transection, stretching, or compression)), post-traumatic pain, arthritic pain (rheumatoid; or osteoarthritis (i.e. joint pain and stiffness due to gradual deterioration of the joint cartilage; risk factors include aging, injury, and obesity; commonly affected joints are the hand, wrist, neck, knee, hip, and spine), pain and pain associated with damage to joints, muscle, and tendons as in axial low back pain (i.e. a prevalent, painful condition affecting the lower portion of the back; common causes include muscle strain, spine fracture, bulging or ruptured disc, and arthritis), severe nociceptive pain may transition to inflammatory pain if there is associated tissue injury.

Neuropathic pain is a common type of chronic, non-malignant pain, which is the result of an injury or malfunction in the peripheral or central nervous system and serves no protective biological function. It is estimated to affect more than 1.6 million people in the U.S. population. Neuropathic pain has many different etiologies, and may occur, for example, due to trauma, surgery, herniation of an intervertebral disk, spinal cord injury, diabetes, infection with herpes zoster (shingles), HIV/AIDS, late-stage cancer, amputation (including mastectomy), carpal tunnel syndrome, chronic alcohol use, exposure to radiation, and as an unintended side-effect of neurotoxic treatment agents, such as certain anti-HIV and chemotherapeutic drugs. Peripheral neuropathy is caused by damages to the peripheral nerves from injury, trauma, prolonged pressure, or inflammation causing numbness and pain in corresponding areas of the body.

Neuropathic pain is frequently described as “burning,” “electric,” “tingling,” or “shooting” in nature. It is often characterized by chronic dynamic allodynia (defined as pain resulting from a moving stimulus that does not ordinarily elicit a painful response, such as light touch) and hyperalgesia (defined as an increased sensitivity to a normally painful stimulus) and may persist for months or years beyond the apparent healing of any damaged tissues.

Pain may occur in patients with cancer, which may be due to multiple causes; inflammation, compression, invasion, metastatic spread into bone or other tissues.

There are some conditions where pain occurs in the absence of a noxious stimulus, tissue damage or a lesion to the nervous system, called dysfunctional pain and these include but are not limited to fibromyalgia, tension type headache, and irritable bowel disorders.

Migraine is a headache associated with the activation of sensory fibers innervating the meninges of the brain.

Itch (pruritus) is a dermatological condition that may be localized and generalized and can be associated with skin lesions (rash, atopic eczema, wheals). Itch accompanies many conditions including but not limited to stress, anxiety, UV radiation from the sun, metabolic and endocrine disorders (e.g., liver or kidney disease, hyperthyroidism), cancers (e.g., lymphoma), reactions to drugs or food, parasitic and fungal infections, allergic reactions, diseases of the blood (e.g., polycythemia vera), and dermatological conditions. Itch is mediated by a subset of small diameter primary sensory neurons, the pruriceptor, that share many features of nociceptor neurons, including, but not limited to, expression of TRPV1 channels, and other large pore channels (e.g. TRPV2-4, TRPA1, TRPM8, ASIC and P2X(2/3). Certain itch mediators, such as eicosanoids, histamine, bradykinin, ATP, and various neurotrophins have endovanilloid functions. Topical capsaicin suppresses histamine-induced itch. Pruriceptors like nociceptors are therefore a suitable target for this method of delivering ion channel blockers.

Cough is a defensive reflex designed to protect the airway from foreign bodies and to aid in the clearance of luminal debris. This reflex, however, can became aberrant in a number of diseases leading to a non-productive dry cough where hyper- or allo-tussive states exist. Hyper- and allo-tussive states are often chronic in nature lasting greater than three months and can be manifested in many airway diseases states including asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF) and lung cancer. In addition, inappropriate cough reflexes can be manifested acutely and chronically following viral infection. Furthermore, chronic cough can be idiopathic in nature with unknown etiology.

Neurogenic inflammation is a mode of inflammation mediated by the efferent (motor) functions of sensory neurons, in which pro-inflammatory mediator molecules released in the periphery by pain-sensing neurons (nociceptors) both activate a variety of inflammatory pathways in immune cells, and also act on the vascular system to alter blood flow and capillary permeability.

Neurogenic inflammation contributes to the peripheral inflammation elicited by tissue injury, autoimmune disease, infection, allergy, exposure to irritants in a variety of tissues, and is thought to play an important role in the pathogenesis of numerous disorders (e.g. migraine, arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn). One way to reduce neurogenic inflammation is to block excitability in nociceptors, thereby preventing the activation of nociceptor peripheral terminals and the release of pro-inflammatory chemicals.

Despite the development of a variety of therapies for pain, itch, and neurogenic inflammation, there is a need for additional agents.

SUMMARY OF THE INVENTION

The present invention provides compounds represented by Formula (I) that can be used to inhibit nociceptors and/or to treat or prevent pain, itch, and neurogenic inflammation:

wherein:

Y⁻ is a pharmaceutically acceptable anion;

R^(A), R^(B), and R^(C) are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR^(I), NR^(J)R^(K), NR^(L)C(O)R^(M), CN, S(O)R^(N), S(O)₂R^(N), SO₂R^(O)R^(P), S₂NR^(Q)R^(R), SO₃R^(S), CO₂R^(T), C(O)R^(U), and C(O)NR^(V)R^(W);

each of R^(I), R^(J), R^(K), R^(L), R^(M), R^(N), R^(O), R^(P), R^(Q), R^(R), R^(S), R^(T), R^(U), R^(V), and R^(W) is independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl;

X¹ is selected from —CR^(X)R^(Y)—, —N^(Z)C(O)—, —NR^(Z)C(O)CR^(X)R^(Y)—, —OC(O)—, —SC(O)—, —C(O)NR^(1A)—, —C(O)O—, —C(O)—, —(O)CS—, —NR^(1A)S(O)—, —S(O)NR^(1A)—, —NR^(1A)C(O)NR^(1A)—, —S(O)— and —S(O)₂—;

each of R^(X), R^(Y), R^(Z), and R^(1A) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or R^(X), R^(Y), R^(Z), or R^(1A) together with R^(D) or R^(E) and the atoms to which they are attached form an optionally substituted cycloalkyl (such as a C₃-C₆ cycloalkyl) or an optionally substituted heterocyclic ring (such as a 3- to 15-membered heterocyclic ring);

each of R^(D) and R^(E) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R^(D) and R^(E) together with the carbon to which they are attached form a substituted or unsubstituted cycloalkyl (such as a C₃-C₆ cycloalkyl) or a substituted or unsubstituted heterocyclic (such as a 3- to 15-membered heterocyclic ring);

each of R^(F), R^(G) and R^(H) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted —C₆-C₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted —CH₂—C₅-C₁₀ aryl, and substituted or unsubstituted —CH₂—C₅-C₁₀ heteroaryl; or alternatively, two or three of R^(F), R^(G) and R^(H) together with the P⁺ to which they are attached form an optionally substituted heterocyclyl (such as a 3- to 15-membered heterocyclic ring) having, zero, one or more heteroatoms in addition to the P⁺, including, but not limited to, an optionally substituted heteroaryl ring;

or two or three of R^(D), R^(E), R^(F), R^(G) and R^(H) together with the P⁺ form an optionally substituted heterocyclic ring having, zero, one or more heteroatoms in addition to the P⁺, including but not limited to, a heteroaryl ring; for example, two of R^(E), R^(F), and R^(G) are taken together with the P⁺ to form a heterocyclic ring having, zero, one or more heteroatoms in addition to the P⁺.

The invention further relates to phosphonium derivatives of sodium channel blocker compounds comprising an amine group (for example, a caine compound) wherein the amine of the sodium channel blocker compound is replaced by a phosphonium. Examples of sodium channel blocker compounds include, but are not limited to, lidocaine, bupivacaine, mepivacaine, etidocaine, prilocaine, tocainide, ropivacaine, proparacaine, allocaine, encainide, procainamide, metoclopramide, flecainide, tetracaine, benzocaine, oxybuprocaine, butambine, propoxycaine, dyclonine, pramocaine, chloroprocaine, proparacaine, piperocaine, hexylcaine, naepaine, cyclomethylcaine, and dibucaine, articaine, mexiletine, bupropion, ambroxol, procaine, tolperinone, and substituted derivatives thereof.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE illustrates the voltage protocol used in the Whole Cell Patch Clamp Protocol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds represented by Formula (I) as described herein, as well as pharmaceutically acceptable salts, stereoisomers, solvates, hydrates or combinations thereof. The invention also provides compositions comprising compounds having Formula (I) or pharmaceutically acceptable salts thereof, for example, compositions comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The compositions of the invention may further comprise compounds of the invention and a biologically active agent. The compositions described herein can be formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration.

The invention further provides methods for treating pain, itch, or a neurogenic inflammatory disorder in a patient, including administering to the patient an effective amount of a compound described herein or a composition comprising an effective amount of a compound having Formula (I), wherein the compound inhibits one or more voltage-gated ion channels present in nociceptors and/or cough receptors and/or pruriceptors when exposed or applied to the internal face of the channels but does not substantially inhibit the channels when applied to the external face of the channels, and wherein the compound is capable of entering nociceptors, cough receptors or pruriceptors through a large pore channel when the channel is activated and inhibiting one or more voltage-gated ion channels present in the nociceptors cough receptors or pruriceptors.

In certain embodiments, the large pore channel is a transient receptor potential ion channel (TRP channel). In other embodiments, the TRP channel is activated by an exogenous or endogenous agonist. In yet other embodiments, the large pore channel is TRPA1, TRPV1-4, TRPM8, ASIC or P2X. In particular embodiments, the compound is capable of entering nociceptors, cough receptors or pruriceptors through the TRPA1 TRPV1-4, TRPM8, ASIC or P2X receptor/channel when the receptor/channel is activated. In yet other embodiments, the compound inhibits voltage-gated sodium channels. In yet other embodiments, the type of pain treated by the methods, compositions, and kits of the invention is selected from the group consisting of neuropathic pain, inflammatory pain, nociceptive pain, pain due to infections, and procedural pain, or wherein the neurogenic inflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis, and atopic dermatitis.

We have identified compounds having Formula (I)

that are capable of passing through open large pore channels that are expressed on nociceptors and/or cough receptors and/or pruriceptors but not on motor neurons. Because the ion channel blocking compounds of the present invention are positively charged, they are not membrane-permeable and thus cannot enter cells that do not express large pore channels. Since large pore channels are often more active in tissue conditions associated with pain (such as inflammation) due to release of endogenous ligands or activation by thermal stimuli, the ion channel blocker of the invention can be used alone to selectively target activated nociceptors in order to effectively treat (e.g., eliminate or alleviate) pain, cough, itch, or neurogenic inflammation. The ion channel blockers of the invention can also be used in combination with one or more exogenous large pore channel agonists to selectively target nociceptors in order to effectively treat (e.g., eliminate or alleviate) pain, itch, or neurogenic inflammation.

Voltage-dependent ion channels in pain-sensing neurons are currently of great interest in developing drugs to treat pain. Blocking voltage-dependent sodium channels in pain-sensing neurons can block pain signals by interrupting initiation and transmission of the action potential. Moreover, blocking voltage-dependent sodium channels in nociceptors can reduce or eliminate neurogenic inflammation by preventing activation of nociceptor peripheral terminals and the release thereof pro-inflammatory chemicals.

Heretofore, a limitation in treating with molecules that block sodium channels or calcium channels is that the vast majority of such externally-applied molecules are hydrophobic and can pass through membranes. Because of this, they will enter all cells and thus have no selectivity for affecting only nociceptors.

The inhibitors of the present invention are membrane-impermeable and are only effective when present inside the nociceptor cell, and thus must pass through the cell membrane via a channel or receptor, such as large pore channels (e.g., TRPAV1-4, TRPA1, TRPM8, ASIC and P2X(2/3)), in order to produce an effect. Under normal circumstances, most large pore channels in nociceptors are not active but require a noxious thermal, mechanical, or chemical stimulus to activate them. For example, TRP channels in nociceptors can be activated by an exogenous TRP ligand (i.e. TRP agonist) such as capsaicin, which opens the TRPV1 channel. Thus, one approach to selectively targeting nociceptors is to co-administer the membrane-impermeable ion channel inhibitor with an exogenous TRP ligand that permits passage of the inhibitor through the TRP channel into the cell. In addition to capsaicin, the exogenous TRP ligand can also be another capsaicinoid, mustard oil, or lidocaine. In another example, TRP channels may be active in response to exogenous irritant activators such as inhaled acrolein from smoke or chemical warfare agents such as tear gas.

Under certain circumstances, large pore channels can be activated in the absence of exogenous large pore channel agonists/ligands by endogenous inflammatory activators that are generated by tissue damage, infection, autoimmunity, atopy, ischemia, hypoxia, cellular stress, immune cell activation, immune mediator production, and oxidative stress. Under such conditions, endogenous molecules (e.g., protons, lipids, and reactive oxygen species) can activate large pore channels expressed on nociceptors, allowing membrane-impermeable, voltage-gated ion channel blockers to gain access to the inside of the nociceptor through the endogenously-activated large pore channels. Endogenous inflammatory activators of large pore channels include, for example, prostaglandins, nitric oxide (NO), peroxide (H₂O₂), cysteine-reactive inflammatory mediators like 4-hydroxynonenal, endogenous alkenyl aldehydes, endocannabinoids, and immune mediators (e.g., interleukin 1 (IL-1), nerve growth factor (NGF), and bradykinin, whose receptors are coupled to large pore channels).

Definitions

As used herein, the words “a” and “an” are meant to include one or more unless otherwise specified.

By “biologically active” is meant that a molecule, including biological molecules, such as nucleic acids, peptides, polypeptides, proteins, exerts a biological, physical, or chemical effect on a protein, enzyme, receptor, ligand, antigen, itself or other molecule. For example, a “biologically active” molecule may possess, e.g., enzymatic activity, protein binding activity, or pharmacological activities.

Biologically active agents that can be used in the methods and kits described herein include, without limitation, TRP1A receptor agonists, TRPV1-4 receptor agonists, ASIC agonists, TRPM8 agonists, P2X receptor agonists, NSAIDs, glucocorticoids, narcotics, anti-proliferative and immune modulatory agents, an antibody or antibody fragment, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, and a vaccine.

By “inflammation” is meant any types of inflammation, such those caused by the immune system (immune-mediated inflammation) and by the nervous system (neurogenic inflammation), and any symptom of inflammation, including redness, heat, swelling, pain, and/or loss of function.

By “neurogenic inflammation” is meant any type of inflammation mediated or contributed to by neurons (e.g. nociceptors) or any other component of the central or peripheral nervous system.

The term “pain” is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g. somatic pain and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain.

The term “nociceptive pain” is used to include all pain caused by noxious stimuli that threaten to or actually injure body tissues, including, without limitation, by a cut, bruise, bone fracture, crush injury, burn, and the like. Pain receptors for tissue injury (nociceptors) are located mostly in the skin, musculoskeletal system, or internal organs.

The term “somatic pain” is used to refer to pain arising from bone, joint, muscle, skin, or connective tissue. This type of pain is typically well localized.

The term “visceral pain” is used herein to refer to pain arising from visceral organs, such as the respiratory, gastrointestinal tract and pancreas, the urinary tract and reproductive organs. Visceral pain includes pain caused by tumor involvement of the organ capsule. Another type of visceral pain, which is typically caused by obstruction of hollow viscus, is characterized by intermittent cramping and poorly localized pain. Visceral pain may be associated with inflammation as in cystitis or reflux esophagitis.

The term “inflammatory pain” includes pain associates with active inflammation that may be caused by trauma, surgery, infection and autoimmune diseases.

The term “neuropathic pain” is used herein to refer to pain originating from abnormal processing of sensory input by the peripheral or central nervous system consequent on a lesion to these systems.

The term “procedural pain” refers to pain arising from a medical, dental or surgical procedure wherein the procedure is usually planned or associated with acute trauma.

The term “itch” is used herein in the broadest sense and refers to all types of itching and stinging sensations localized and generalized, acute intermittent and persistent. The itch may be idiopathic, allergic, metabolic, infectious, drug-induced, due to liver, kidney disease, or cancer. “Pruritus” is severe itching.

By “patient” is meant any animal. In one embodiment, the patient is a human. Other animals that can be treated using the methods, compositions, and kits of the invention include, but are not limited to, non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).

Compounds useful in the invention include, but are not limited to, those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein. The term “pharmaceutically acceptable anion” as used herein, refers to the conjugate base of a pharmaceutically acceptable acid. Such acids are described in Stahl, P. H. and Wermuth, C. G. (eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley VCH (2008). Pharmaceutically acceptable acids include, but are not limited to, acetic acid, dichloroacetic acid, adipic acid, alginic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, 4-acetamidobenzoic acid, benzoic acid, p-bromophenylsulfonic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, sulfuric acid, boric acid, citric acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, (−)-L-pyroglutamic acid, salicyclic acid, 4-aminosalicyclic acid, sebacic acid, stearic acid, succinic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid. Pharmaceutically acceptable anions include the conjugate base of any the acids set forth above.

The term “pharmaceutically acceptable salt” represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like.

In the generic descriptions of compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 4 carbon atoms or C₁-C₄ alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alkyl group from 1 to 4 carbon atoms includes each of C₁, C₂, C₃, and C₄. Other numbers of atoms and other types of atoms may be indicated in a similar manner.

“D” is deuterium.

As used herein, the terms “alkyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic, and preferably have from 3 to 6 ring carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. By “C₁-alkyl” is meant a branched, unbranched or cyclic hydrocarbon group having from 1 to * carbon atoms, where * is an integer, such as 2, 3, 4, 5, 6, 7, 8, 10, 12, or more. An alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. In certain aspects, the alkyl is a C₁-C₆ alkyl. C₁₆ alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl and cyclohexyl. Another specific example of a substituted alkyl is:

Another example of a substituted alkyl is a heteroalkyl. By “heteroalkyl” is meant a branched or unbranched alkyl, cycloalkyl, alkenyl, or alkynyl group having from 1 to 7 or more carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls can include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of C₁₋₇ heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.

An alkenyl is a branched or unbranched hydrocarbon group containing one or more double bonds. For example, by “C₂₋₆ alkenyl” or “C₂-C₆ alkenyl” is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 6 carbon atoms. An alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The alkenyl group may be substituted or unsubstituted. Exemplary substituents include those described above for alkyl, and specifically include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, and carboxyl groups. C₂₋₆ alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.

An alkynyl is a branched or unbranched hydrocarbon group containing one or more triple bonds. For example, by “C₂₋₆ alkynyl” or “C₂-C₆ alkynyl” is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 6 carbon atoms. An alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The alkynyl group may be substituted or unsubstituted. Exemplary substituents those described above for alkyl, and specifically include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, and carboxyl groups. C₂₋₆ alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

By “heterocyclyl,” “heterocyclic,” or “heterocycloalkyl” is meant a stable monocyclic or a polycyclic (including a bicyclic or a tricyclic) heterocyclic ring which is saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic), and which consists of 2 or more carbon atoms and 1, 2, 3 4 or more heteroatoms independently selected from P, N, O, and S and including any bicyclic or polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. In certain aspects, the heterocyclyl is a 3- to 15-membered ring system, a 3- to 12-membered ring system, or a 3- to 9-membered ring system. The heterocyclyl (including heteroaryl groups) may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via a heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A nitrogen or phosphorus atom in the heterocycle can be quaternized. Preferably when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl.

Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, quinolinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl. Preferred substituents include phenyl, methyl, ethyl, propyl, butyl, oxo, chloro, bromo, fluoro and iodo.

By “aryl” is meant an aromatic group having a ring system comprised of carbon atoms with conjugated 7 electrons (e.g., phenyl). A “C₆-C₁₂ aryl” or “C₆-C₁₀ aryl” is an aryl group has from 6 to 12 carbon atoms or 6 to 10 carbon atoms, respectively. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

By “aralkyl” is meant a substituted or unsubstituted alkyl that is substituted by a substituted or unsubstituted aryl (including, for example, (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl). By “heteroaralkyl” is meant a substituted or unsubstituted alkyl that is substituted by or heteroaryl group.

By “halide” or “halogen” is meant bromine, chlorine, iodine, or fluorine.

By “fluoroalkyl” is meant an alkyl group that is substituted with one or more fluorine atoms, such as a perfluoroalkyl group. Trifluoromethyl, difluoromethyl, fluoromethyl and heptafluoroethyl are examples.

By “alkoxy” is meant a chemical moiety with the formula —O—R, wherein R is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

By “alkylcarboxy” is meant a chemical moiety with the formula —(R)—COOH, wherein R is selected from alkyl (e.g. C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl), heterocyclyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, or heteroalkyl, each optionally substituted.

By “charged moiety” is meant a moiety which gains a proton at physiological pH thereby becoming positively charged (e.g., ammonium, guanidinium, or amidinium) or a moiety that includes a net formal positive charge without protonation (e.g., phosphonium and quaternary ammonium). The charged moiety may be either permanently charged or transiently charged.

By “therapeutically effective amount” or “effective amount” is meant an amount sufficient to produce a desired result, for example, the reduction or elimination of pain, itch, or neurogenic inflammation in a patient (e.g., a human) suffering from a condition, disease, or illness that is caused wholly or in part by neurogenic inflammation (e.g. asthma, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, chronic refractory cough, post-viral cough, gastritis, migraine headache, psoriasis, rhinitis, rosacea, or sunburn).

“Solvates” means solvent addition forms that contain either stoichiometric or nonstoichiometric amounts of solvent, including hydrates.

The compounds of the present invention, including salts of the compounds, can exist in unsolvated forms as well as solvated forms, including hydrated forms and unhydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Nonlimiting examples of hydrates include monohydrates, dihydrates, hemihydrates, etc. In certain aspects, the compound is a hemihydrate. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

The compounds of the invention may exist in multiple crystalline (polymorphs) or amorphous forms. In general, any physical forms can be used in the present invention and are intended to be within the scope of the invention. Stable crystalline forms are preferred.

The invention further relates to phosphonium derivatives of sodium channel blocker compounds comprising an amine group (for example, a caine compound) wherein the amine of the sodium channel blocker is replaced by a phosphonium. Examples of caine compounds include, but are not limited to, lidocaine, bupivacaine, mepivacaine, etidocaine, prilocaine, tocainide, ropivacaine, proparacaine, allocain, encainide, procainamide, metoclopramide, flecainide, tetracaine, benzocaine, oxybuprocaine, butambine, propoxycaine, dyclonine, pramocaine, chloroprocaine, proparacaine, piperocaine, hexylcaine, naepaine, cyclomethylcaine, and bipucaine, and substituted derivatives thereof.

Compounds that can be used in the compositions, kits, and methods of the invention include compounds having Formula (I), or a pharmaceutically acceptable salt:

wherein

Y⁻ is a pharmaceutically acceptable anion and the other variables are as defined herein.

Preferred embodiments of the variables are also provided. It is intended that each preferred selection can be combined with one or other preferred selections (combining between two or more list) as though this specification offered each and every possible combination and permutation in the alternative.

R^(A), R^(B), and R^(C) are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR^(I), NR^(J)R^(K), NR^(L)C(O)R^(M), S(O)R^(N), S(O)₂R^(N), SO₂R^(O)R^(P), SO₂NR^(Q)R^(R), SO₃R^(S), CO₂R^(T), C(O)R^(U), and C(O)NR^(V)R^(W); and wherein each of R^(I), R^(J), R^(K), R^(L), R^(M), R^(N), R^(O), R^(P), R^(Q), R^(R), R^(S), R^(T), R^(U), R^(V), and R^(W) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl. In certain aspects, R^(A), R^(B), and R^(C) are preferably independently selected from H, D, halogen, alkoxy, substituted or unsubstituted C₁-C₄ alkyl, and NR^(J)R_(K); and each of R and R^(K) is independently selected from H and substituted or unsubstituted C₁-C₄ alkyl. In yet additional preferred aspects, R^(A), R^(B), and R^(C) are independently selected from H, D, halogen, OR^(I), substituted or unsubstituted C₁-C₄ alkyl, and NR^(J)R^(K); wherein each of R^(I), R^(J) and R^(K) is independently selected from H and substituted or unsubstituted C₁-C₄ alkyl. In a preferred embodiment, each of R^(A) and R^(B) is CH₃, and R^(C) is selected from the group consisting of H, CH₃, halogen, nitrile (cyano), methoxy, and ethoxy. In further preferred embodiments, each of R^(A) and R^(B) is CH₃, and R^(C) is selected from the group consisting of H, CH₃, fluoro, chloro, nitrile, methoxy, and ethoxy. In additional preferred embodiments, each of R^(A) and R^(B) are CH₃ and R^(C) is hydrogen.

X¹ is selected from —CR^(X)R^(Y)—, —NR^(Z)C(O)—, —NR^(Z)C(O)CR^(X)R^(Y)—, —OC(O)—, —SC(O)—, —C(O)NR^(1A)—, —C(O)O—, —C(O)—, —(O)CS—, —NR^(1A)S(O)—, —S(O)NR^(1A)—, —NR^(1A)C(O)NR^(1A)—, —S(O)— and —S(O)₂—; and each of R^(X), R^(Y), R^(Z), and R^(1A) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl. In a preferred embodiment, X¹ is —NR^(Z)C(O)—. In additional preferred embodiments, R^(Z) is hydrogen. In yet an additional preferred embodiment, X¹ is —NR^(Z)C(O)— and R^(Z) is hydrogen. In certain preferred embodiments, X¹ is —NHC(O)— or —C(O)NH—.

Each of R^(D) and R^(E) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl; or R^(D) and R^(E) together form a substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted heterocyclic. In certain preferred embodiments, R^(D) and R^(E) are both hydrogen. In yet additional preferred embodiments, R^(D) is hydrogen and R^(E) is an alkyl, for example, a C₁-C₆ alkyl or a C₁-C₄ alkyl including, but not limited to, methyl, ethyl, propyl and butyl. In certain additional preferred embodiments, R^(D) and R^(E) are taken together with the carbon to which they are attached to form a C₃-C₆ cycloalkyl including, but not limited to, cyclopropyl or cyclobutyl. In yet other preferred embodiments, R^(D) is hydrogen and R^(E) is taken together with R^(F) to form a heterocyclic ring, preferably having 5 or 6 ring atoms.

Each of R^(F), R^(G) and R^(H) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted —C₆-C₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted —CH₂—C₆-C₁₀ aryl and a substituted or unsubstituted —CH₂-5- to 10-membered heteroaryl. In certain preferred embodiments, each of R^(F), R^(G) and R^(H) are the same or different and is a substituted or unsubstituted alkyl, such as methyl, ethyl, n-propyl, and n-butyl. In further preferred embodiments, each of R^(F), R^(G) and R^(H) is the same and is a substituted or unsubstituted alkyl, such as methyl, ethyl, n-propyl, and n-butyl. In yet other preferred embodiments, each of R^(F), R^(G) and R^(H) is ethyl. In yet other preferred embodiments, one, two or three of R^(F), R^(G) and R^(H) is independently an aryl group (preferably, phenyl), aralkyl (preferably, benzyl, or a heteroaralkyl. In yet additional preferred aspects, each of R^(F), R^(G) and R^(H) is phenyl. In yet additional preferred embodiments, R^(H) is an aryl (preferably, phenyl), aralkyl (preferably, benzyl), and R^(F) and R^(G) are the same or different and are each independently a substituted or unsubstituted alkyl, such as a substituted or unsubstituted C₁-C₆ alkyl or a substituted or unsubstituted C₁-C₄ alkyl, including, for example, methyl, ethyl, n-propyl, and n-butyl; preferably ethyl. In yet additional preferred embodiments, at least one of R^(F), R^(G), and R^(H) is

As will be understood, wherein one of R^(F), R^(G), and R^(H) is the radical above, then the compound of Formula (I) is a dimer; for example, a symmetric or asymmetric dimer or trimer (around the P atom). In yet further preferred embodiments, R^(F) and R^(G) are the same or different and are each a substituted or unsubstituted alkyl, such as methyl or ethyl, and R^(H) is:

In certain additional preferred embodiments, R^(F) and R^(G) are the same or different and are each a substituted or unsubstituted alkyl, such as methyl or ethyl, and R^(H) is:

In certain aspects, two or three of R^(F), R^(G) and R^(H) together with the P⁺ to which they are attached form an optionally substituted heterocyclic ring having, zero, one, or more heteroatoms in addition to the P⁺. In certain preferred aspects, the heterocyclyl has 5, 6, or 7 ring atoms (in other words, is 5-, 6-, or 7-membered). In further preferred embodiments, the optionally substituted heterocyclic is an optionally substituted heteroaryl. In yet additional preferred embodiments, two of R^(F), R^(G) and R^(H) together with P⁺ to which they are attached form an optionally substituted heterocyclic ring having, zero, one, or more heteroatoms in addition to the P⁺. In additional preferred aspects, R^(F) and R^(G) are taken together with the P⁺ to which they are attached to form a heterocyclyl having 5, 6 or 7 ring atoms, and R^(H) is an aralkyl or a heteroaralkyl. In yet further preferred aspects, R^(F) and R^(G) together with the P⁺ to which they are attached form an optionally substituted heterocyclic ring having, zero, one, or more heteroatoms in addition to the P⁺, and R^(H) is —CH₂—Z; wherein Z is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; preferably, Z is selected from the group consisting of unsubstituted phenyl; phenyl substituted by a C₁-C₄ alkyl (for example, methyl, ethyl, n-propyl, and n-butyl), halogen (for example, fluoro or chloro), methoxy, ethoxy, and cyano; substituted or unsubstituted heteroaryl. Preferably, Z is selected from Tables 1, 2, and 3 below.

Two or three of R^(D), R^(E), R^(F), R^(G) and R^(H) can also be taken together with the P⁺ to form an optionally substituted heterocyclic ring having, zero, one, or more heteroatoms in addition to the P⁺. Such heterocyclic rings include, but are not limited to, heteroaryl rings. Preferably the heterocyclic ring has 5, 6, or 7 ring members. In some preferred aspects, the heterocyclyl ring has 4, 5, or 6 carbons. Preferably two of R^(E), R^(F), and R^(G) are taken together with the P⁺ form a heterocyclic ring. In yet additional preferred embodiments, two of R^(E), R^(F), and R^(G) are taken together with the P⁺ form a heterocyclic ring and R^(D) is hydrogen. In yet further preferred embodiments, two of R^(E), R^(F), and R^(G) are taken together with the P⁺ to form a heterocyclic ring, R^(D) is optionally hydrogen, and R^(G) and R^(H) are alkyl, such as methyl, ethyl, propyl and butyl. In yet further embodiments, two of R^(E), R^(F), and R^(G) are taken together with the P⁺ to form a heterocyclic ring, R^(D) is optionally hydrogen, and R^(G) and/or R^(H) are aralkyl, such as benzyl, or heteroaralkyl.

In yet additional aspects, R^(X), R^(Y), R^(Z), or R^(1A) together with R^(D) or R^(E), form an optionally substituted heterocyclic ring; preferably, having 5, 6 or 7 ring atoms.

In preferred embodiments, R^(F) and R^(G) together with the P to which they are attached form a substituted or unsubstituted five, six, or seven-membered phosphorus-containing heterocyclic ring, including but not limited to:

In another embodiment, each of R^(F), R^(G) and R^(H) is independently selected from phenyl, CH₃, CH₂CH₃, (CH₂)₂CH₃, (CH₂)₃CH₃, and (CH₂)₄CH₃. In another embodiment, each of R^(F), R^(G) and R^(H) is the same and selected from phenyl, CH₃, CH₂CH₃, (CH₂)₂CH₃, (CH₂)₃CH₃, and (CH₂)₄CH₃.

In some embodiments Y⁻ is a halide anion, a carboxylate, or a sulfonate. Y⁻ can, for example, be a halide ion, a substituted or unsubstituted alkylsulfonate, a substituted or unsubstituted arylsulfonate, a substituted or unsubstituted alkyl or aliphatic carboxylate, a substituted or unsubstituted aryl carboxylate, or a substituted or unsubstituted heterocyclyl carboxylate.

In certain embodiments, Y⁻ is selected from the group consisting of trifluoroacetate, sulfate, phosphate, acetate, fumarate, formate, carbonate, maleate, citrate, pyruvate, succinate, oxalate, a sulfonate, (for example, methanesulfonate, trifluoromethanesulfonate, toluenesulfonate such as p-toluenesulfonate, benzenesulfonate, ethanesulfonate, camphorsulfonate, 2-mesitylenesulfonate, or naphthalenesulfonate such as 2-naphthalenesulfonate), bisulfate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isethionate (2-hydroxyethylsulfonate), D-mandelate, L-mandelate, propionate, tartarate, phthalate, hydrochlorate, hydrobromate, and nitrate. In one embodiment, Y⁻ is a halide anion.

In a preferred embodiment, the Y⁻ anion is selected from the halide ions bromide, chloride, or iodide.

In certain preferred embodiments, the present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R^(H) is an optionally substituted —CH₂-aryl or optionally substituted —CH₂-heteroaryl selected from one of the following:

Each preferred embodiment described herein can be taken in combination with one, any or all other preferred embodiments, as though presented here in every permutation.

In certain aspects, the compound is selected from those shown in the Table A below, or a pharmaceutically acceptable salt thereof, wherein Y⁻ is a pharmaceutically acceptable anion:

TABLE A Compound # STRUCTURE 1

2

3

4

5

6

7

8

9

10

In yet additional aspects, the compound is selected from those shown in Table B below, or pharmaceutically acceptable salt thereof.

TABLE B Compound # STRUCTURE 1A

1B

2A

3A

3B

4A

4B

5A

5B

6A

7A

7B

8A

9A

10A

Representative compounds according to the invention and their enantiomers and pharmaceutically acceptable salts thereof are those selected from Table C below, wherein Y⁻ is a pharmaceutically acceptable anion, as defined above, and Z is selected from one of the structures in Tables 1-3.

TABLE C Representative Compounds of the Invention No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

TABLE 1 Representative Z Structures No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

TABLE 2 Representative Z Structures No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

TABLE 3 Representative Z Structures No. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

Representative compounds according to the invention and their enantiomers and pharmaceutically acceptable salts thereof are those further selected from Table C below, wherein Y− is a pharmaceutically acceptable anion, as defined above.

TABLE C

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

Preferred compounds according to the invention and their enantiomers and pharmaceutically acceptable salts thereof are represented by Formula (II),

wherein the preferred substituent combinations R^(C), R^(D), P⁺/R^(F)/R^(G) and Z are as defined in Table 4, and Y⁻ is a pharmaceutically acceptable anion as defined above. The compounds can be made according to the methods generally described below.

TABLE 4 Preferred Combinations of R^(C), R^(D), P⁺/R^(f/)R^(G), and Z Substituents according to Formula (II). Combination Number R^(C) R^(D) P⁺/R^(F)/R^(G) Z 1 H H

2 Cl H

3 CH₃ H

4 H CH₃

5 Cl CH₃

6 CH₃ CH₃

7 H CH₂CH₃

8 Cl CH₂CH₃

9 CH₃ CH₂CH₃

10 H (CH₂)₂CH₃

11 Cl (CH₂)₂CH₃

12 CH₃ (CH₂)₂CH₃

13 H H

14 Cl H

15 CH₃ H

16 H CH₃

17 Cl CH₃

18 CH₃ CH₃

19 H CH₂CH₃

20 Cl CH₂CH₃

21 CH₃ CH₂CH₃

22 H (CH₂)₂CH₃

23 Cl (CH₂)₂CH₃

24 CH₃ (CH₂)₂CH₃

25 H H

26 Cl H

27 CH₃ H

28 H CH₃

29 Cl CH₃

30 CH₃ CH₃

31 H CH₂CH₃

32 Cl CH₂CH₃

33 CH₃ CH₂CH₃

34 H (CH₂)₂CH₃

35 Cl (CH₂)₂CH₃

36 CH₃ (CH₂)₂CH₃

37 H H

38 Cl H

39 CH₃ H

40 H CH₃

41 Cl CH₃

42 CH₃ CH₃

43 H CH₂CH₃

44 Cl CH₂CH₃

45 CH₃ CH₂CH₃

46 H (CH₂)₂CH₃

47 Cl (CH₂)₂CH₃

48 CH₃ (CH₂)₂CH₃

49 H H

50 Cl H

51 CH₃ H

52 H CH₃

53 Cl CH₃

54 CH₃ CH₃

55 H CH₂CH₃

56 Cl CH₂CH₃

57 CH₃ CH₂CH₃

58 H (CH₂)₂CH₃

59 Cl (CH₂)₂CH₃

60 CH₃ (CH₂)₂CH₃

61 H H

62 Cl H

63 CH₃ H

64 H CH

65 Cl CH₃

66 CH₃ CH₃

67 H CH₂CH₃

68 Cl CH₂CH₃

69 CH₃ CH₂CH₃

70 H (CH₂)₂CH₃

71 Cl (CH₂)₂CH₃

72 CH₃ (CH₂)₂CH₃

73 H H

74 Cl H

75 CH₃ H

76 H CH₃

77 Cl CH₃

78 CH₃ CH₃

79 H CH₂CH₃

80 Cl CH₂CH₃

81 CH₃ CH₂CH₃

82 H (CH₂)₂CH₃

83 Cl (CH₂)₂CH₃

84 CH₃ (CH₂)₂CH₃

85 H H

86 Cl H

87 CH₃ H

88 H CH₃

89 Cl CH₃

90 CH₃ CH₃

91 H CH₂CH₃

92 Cl CH₂CH₃

93 CH₃ CH₂CH₃

94 H (CH₂)₂CH₃

95 Cl (CH₂)₂CH₃

96 CH₃ (CH₂)₂CH₃

97 H H

98 Cl H

99 CH₃ H

100 H CH₃

101 Cl CH₃

102 CH₃ CH₃

103 H CH₂CH₃

104 Cl CH₂CH₃

105 CH₃ CH₂CH₃

106 H (CH₂)₂CH₃

107 Cl (CH₂)₂CH₃

108 CH₃ (CH₂)₂CH₃

109 H H

110 Cl H

111 CH₃ H

112 H CH₃

113 Cl CH₃

114 CH₃ CH₃

115 H CH₂CH₃

116 Cl CH₂CH₃

117 CH₃ CH₂CH₃

118 H (CH₂)₂CH₃

119 Cl (CH₂)₂CH₃

120 CH₃ (CH₂)₂CH₃

121 H H

122 Cl H

123 CH₃ H

124 H CH₃

125 Cl CH₃

126 CH₃ CH₃

127 H CH₂CH₃

128 Cl CH₂CH₃

129 CH₃ CH₂CH₃

130 H (CH₂)₂CH₃

131 Cl (CH₂)₂CH₃

132 CH₃ (CH₂)₂CH₃

133 H H

134 Cl H

135 CH₃ H

136 H CH₃

137 Cl CH₃

138 CH₃ CH₃

139 H CH₂CH₃

140 Cl CH₂CH₃

141 CH₃ CH₂CH₃

142 H (CH₂)₂CH₃

143 Cl (CH₂)₂CH₃

144 CH₃ (CH₂)₂CH₃

145 H H

146 Cl H

147 CH₃ H

148 H CH₃

149 Cl CH₃

150 CH₃ CH₃

151 H CH₂CH₃

152 Cl CH₂CH₃

153 CH₃ CH₂CH₃

154 H (CH₂)₂CH₃

155 Cl (CH₂)₂CH₃

156 CH₃ (CH₂)₂CH₃

157 H H

158 Cl H

159 CH₃ H

160 H CH₃

161 Cl CH₃

162 CH₃ CH₃

163 H CH₂CH₃

164 Cl CH₂CH₃

165 CH₃ CH₂CH₃

166 H (CH₂)₂CH₃

167 Cl (CH₂)₂CH₃

168 CH₃ (CH₂)₂CH₃

169 H H

170 Cl H

171 CH₃ H

172 H CH₃

173 Cl CH₃

174 CH₃ CH₃

175 H CH₂CH₃

176 Cl CH₂CH₃

177 CH₃ CH₂CH₃

178 H (CH₂)₂CH₃

179 Cl (CH₂)₂CH₃

180 CH₃ (CH₂)₂CH₃

181 H H

182 Cl H

183 CH₃ H

184 H CH₃

185 Cl CH₃

186 CH₃ CH₃

187 H CH₂CH₃

188 Cl CH₂CH₃

189 CH₃ CH₂CH₃

190 H (CH₂)₂CH₃

191 Cl (CH₂)₂CH₃

192 CH₃ (CH₂)₂CH₃

193 H H

194 Cl H

195 CH₃ H

196 H CH₃

197 Cl CH₃

198 CH₃ CH₃

199 H CH₂CH₃

200 Cl CH₂CH₃

201 CH₃ CH₂CH₃

202 H (CH₂)₂CH₃

203 Cl (CH₂)₂CH₃

204 CH₃ (CH₂)₂CH₃

205 H H

206 Cl H

207 CH₃ H

208 H CH₃

209 Cl CH₃

210 CH₃ CH₃

211 H CH₂CH₃

212 Cl CH₂CH₃

213 CH₃ CH₂CH₃

214 H (CH₂)₂CH₃

215 Cl (CH₂)₂CH₃

216 CH₃ (CH₂)₂CH₃

217 H H

218 Cl H

219 CH₃ H

220 H CH₃

221 Cl CH₃

222 CH₃ CH₃

223 H CH₂CH₃

224 Cl CH₂CH₃

225 CH₃ CH₂CH₃

226 H (CH₂)₂CH₃

227 Cl (CH₂)₂CH₃

228 CH₃ (CH₂)₂CH₃

229 H H

230 Cl H

231 CH₃ H

232 H CH₃

233 Cl CH₃

234 CH₃ CH₃

235 H CH₂CH₃

236 Cl CH₂CH₃

237 CH₃ CH₂CH₃

238 H (CH₂)₂CH₃

239 Cl (CH₂)₂CH₃

240 CH₃ (CH₂)₂CH₃

241 H H

242 Cl H

243 CH₃ H

244 H CH₃

245 Cl CH₃

246 CH₃ CH₃

247 H CH₂CH₃

248 Cl CH₂CH₃

249 CH₃ CH₂CH₃

250 H (CH₂)₂CH₃

251 Cl (CH₂)₂CH₃

252 CH₃ (CH₂)₂CH₃

253 H H

254 Cl H

255 CH₃ H

256 H CH₃

257 Cl CH₃

258 CH₃ CH₃

259 H CH₂CH₃

260 Cl CH₂CH₃

261 CH₃ CH₂CH₃

262 H (CH₂)₂CH₃

263 Cl (CH₂)₂CH₃

264 CH₃ (CH₂)₂CH₃

265 H H

266 Cl H

267 CH₃ H

268 H CH₃

269 Cl CH₃

270 CH₃ CH₃

271 H CH₂CH₃

272 Cl CH₂CH₃

273 CH₃ CH₂CH₃

274 H (CH₂)CH₃

275 Cl (CH₂)₂CH₃

276 CH₃ (CH₂)₂CH₃

277 H H

278 Cl H

279 CH₃ H

280 H CH₃

281 Cl CH₃

282 CH₃ CH₃

283 H CH₂CH₃

284 Cl CH₂CH₃

285 CH₃ CH₂CH₃

286 H (CH₂)₂CH₃

287 Cl (CH₂)₂CH₃

288 CH₃ (CH₂)₂CH₃

289 H H

290 Cl H

291 CH₃ H

292 H CH₃

293 Cl CH₃

294 CH₃ CH₃

295 H CH₂CH₃

296 Cl CH₂CH₃

297 CH₃ CH₂CH₃

298 H (CH₂)₂CH₃

299 Cl (CH₂)₂CH₃

300 CH₃ (CH₂)₂CH₃

301 H H

302 Cl H

303 CH₃ H

304 H CH₃

305 Cl CH₃

306 CH₃ CH₃

307 H CH₂CH₃

308 Cl CH₂CH₃

309 CH₃ CH₂CH₃

310 H (CH₂)₂CH₃

311 Cl (CH₂)₂CH₃

312 CH₃ (CH₂)₂CH₃

313 H H

314 Cl H

315 CH₃ H

316 H CH₃

317 Cl CH₃

318 CH₃ CH₃

319 H CH₂CH₃

320 Cl CH₂CH₃

321 CH₃ CH₂CH₃

322 H (CH₂)₂CH₃

323 Cl (CH₂)₂CH₃

324 CH₃ (CH₂)₂CH₃

325 H H

326 Cl H

327 CH₃ H

328 H CH₃

329 Cl CH₃

330 CH₃ CH₃

331 H CH₂CH₃

332 Cl CH₂CH₃

333 CH₃ CH₂CH₃

334 H (CH₂)₂CH₃

335 Cl (CH₂)₂CH₃

336 CH₃ (CH₂)₂CH₃

337 H H

338 Cl H

339 CH₃ H

340 H CH₃

341 Cl CH₃

342 CH₃ CH₃

343 H CH₂CH₃

344 Cl CH₂CH₃

345 CH₃ CH₂CH₃

346 H (CH₂)₂CH₃

347 Cl (CH₂)₂CH₃

348 CH₃ (CH₂)₂CH₃

349 H H

350 Cl H

351 CH₃ H

352 H CH₃

353 Cl CH₃

354 CH₃ CH₃

355 H CH₂CH₃

356 Cl CH₂CH₃

357 CH₃ CH₂CH₃

358 H (CH₂)₂CH₃

359 Cl (CH₂)₂CH₃

360 CH₃ (CH₂)₂CH₃

361 H H

362 Cl H

363 CH₃ H

364 H CH₃

365 Cl CH₃

366 CH₃ CH₃

367 H CH₂CH₃

368 Cl CH₂CH₃

369 CH₃ CH₂CH₃

370 H (CH₂)₂CH₃

371 Cl (CH₂)₂CH₃

372 CH₃ (CH₂)₂CH₃

Compositions of the invention can comprise racemic mixtures, pure enantiomers, or an excess of one enantiomer over the other. For example, a composition can comprise an enantiomeric excess of at least 5, 10, 20, 30, 40, 50, 60, 70, 80 or 90%. In one embodiment, the enantiomeric excess is at least 95%.

The compounds of the invention include all enantiomers which may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, as well as their racemic and optically pure forms, and is not limited to those described herein in any of their pharmaceutically acceptable forms, including enantiomers, salts, solvates, polymorphs, solvatomorphs, hydrates, anhydrous and other crystalline forms and combinations thereof. Likewise, all tautomeric forms are intended to be included.

Preferably, a pharmaceutical composition comprises a compound of the invention as an R enantiomer in substantially pure form; or, a pharmaceutical composition comprises a compound of the invention as an S enantiomer in substantially pure form; or, a pharmaceutical composition comprises a compound of the invention as enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer. It is particularly preferred that the pharmaceutical composition contains a compound of the invention which is a substantially pure optical isomer. For the avoidance of doubt, a compound of the invention can, if desired, be used in the form of solvates.

Synthesis

Compounds having Formula (I) can be prepared using methods analogous to the following general synthetic schemes:

For example,

Additional Biologically Active Agents and Exogenous Large Pore Channel Agonists. As described above, the compound or composition of the invention can be administered with a biologically active agent. For example, one or more additional biologically active agents, including those typically used to treat neurogenic inflammation, may be used in combination with a compound or composition of the invention described herein. The biologically active agents include, but are not limited to, TRP1A receptor agonists, TRPV1-4 receptor agonists, TRPM8 agonists, ASIC agonists, P2X receptor agonists, acetaminophen, NSAIDs, glucocorticoids, narcotics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, anti-proliferative and immune modulatory agents, an antibody or antibody fragment, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, and a vaccine.

TRPV1 agonists that can be employed in the methods, kits and compositions of the invention include, but are not limited to, any that activates TRPV1 receptors on nociceptors and allows for entry of at least one inhibitor of voltage-gated ion channels (for example, a compound of the invention). A suitable TRPV1 agonist is capsaicin or another capsaicinoids, which are members of the vanilloid family of molecules. Naturally occurring capsaicinoids are capsaicin itself, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, and nonivamide. Other suitable capsaicinoids and capsaicinoid analogs and derivatives for use in the compositions and methods of the present invention include naturally occurring and synthetic capsaicin derivatives and analogs including, e.g., vanilloids (e.g., N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, and N-vanillyl-cis-monounsaturated alkenamides), capsiate, dihydrocapsiate, nordihydrocapsiate and other capsinoids, capsiconiate, dihydrocapsiconiate and other coniferyl esters, capsiconinoid, resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamide capsaicin derivatives, olvanil, N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide, N-oleyl-homovanillamide, triprenyl phenols (e.g., scutigeral), gingerols, piperines, shogaols, guaiacol, eugenol, zingerone, nuvanil, NE-19550, NE-21610, and NE-28345. Additional capsaicinoids, their structures, and methods of their manufacture are described in U.S. Pat. Nos. 7,446,226 and 7,429,673, which are hereby incorporated by reference.

Additional suitable TRPV1 agonists include but are not limited to eugenol, arvanil (N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide), JYL79 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol, oleylgingerol, oleylshogaol, and SU200 (N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea). Still other TRPV1 agonists include amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine.

Suitable TRPV2-4 agonists include, but are not limited to, are 2-APB, cannabinol, diphenylboronic anhydride, insulin-like growth factor 1, lysophosphatidylcholine, lysophosphatidylinositol, probenecid, Δ9-tetrahydrocannabinol, vanillin, eugenol, cinnamaldehyde, camphor, carvacrol, thymol, citral, farnesyl diphosphate, tetrahydrocannabivarin, incensole acetate, diphenylboronic anhydride, 6-tert-butyl-m-cresol, dihydrocarveocarveol, borneol, (−)-menthol, GSK1016790A, 4α-PDH, 5,6-epoxyeicosatrienoic acid, 4α-PDD, bisandrographolide, citric acid, phorbol 12-myristate 13-acetate and RN1747.

Suitable TRPM8 agonists include, but are not limited to, are menthol, icilin, eucalyptus, linalool, geraniol, hydroxy-citronellal, WS-3, WS-23, Frescolat MGA, Frescolat ML, PMD 38, CPS125, CoolactP, M8-Ag, AITC, cryosim-3 and Cooling Agent 10.

Suitable ASIC agonists include, but are not limited to, chlorophenylguanidine hydrochloride, GMQ hydrochloride, tetrahydropapaveroline (THP), reticulin, polyamine agmatine, lysophosphatidylcholine, arachidonic acid and neuropeptide SF.

Other biologically active agents which can be employed in the methods, compositions, and kits of the invention include any that activates TRP1A receptors on nociceptors or pruriceptors and allows for entry of at least one inhibitor of voltage-gated ion channels. Suitable TRP1A agonists include but are not limited to cinnamaldehyde, allyl-isothiocynanate (mustard oil), diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, and 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597).

P2X agonists that can be employed in the methods, compositions, and kits of the invention include any that activates P2X receptors on nociceptors or pruriceptors and allows for entry of at least one inhibitor of voltage-gated ion channels. Suitable P2X agonists include, but are not limited to, ATP, α,β-methylene ATP 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, and ATP5′-O-(3-thiotriphosphate).

Other biologically active agents that can be used in combination with the compounds of the invention include NSAIDs, glucocorticoids, narcotics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, anti-proliferative and immune modulatory agents, an antibody or antibody fragment, an antibody, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, and a vaccine.

Non-steroidal anti-inflammatory drugs (NSAIDs) that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited to, acetylsalicylic acid, amoxiprin, benorylate, benorilate, choline magnesium salicylate, diflunisal, ethenzamide, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate, salicylamide, diclofenac, aceclofenac, acemethacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, and the COX-2 inhibitors celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof.

Glucocorticoids that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited to, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, and pharmaceutically acceptable salts thereof.

Narcotics that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited, to tramadol, hydrocodone, oxycodone, morphine, and pharmaceutically acceptable salts thereof.

Antiproliferative and immune modulatory agents that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited to, alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF-alpha agonists, TNF-alpha antagonists or scavengers, interleukin 1 (IL-1) antagonists or scavengers, endothelin A receptor antagonists, retinoic acid receptor agonists, hormonal agents, antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors.

The biologically active agents can be administered prior to, concurrent with, or following administration of a composition of the invention, using any formulation, dosing, or administration known in the art that is therapeutically effective,

Formulation of Compositions

The administration of the compounds of the invention may be by any suitable means that results in the reduction of perceived pain sensation at the target region. The compounds of the invention may be contained in any appropriate amount in any suitable carrier substance and are generally present in amounts totaling 1-99% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intrathecal, epidural, or ocular administration, or by injection, inhalation, or direct contact with the nasal or oral mucosa.

Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 22nd edition, 2013, ed. L. V. Allen, Pharmaceutical Press, Philadelphia, and Encyclopedia of Pharmaceutical Technology, 4^(th) Edition, ed. J. Swarbrick, 2013, CRC Press, New York).

Each compound may be formulated in a variety of ways that are known in the art. For example, a compound of the invention and a biologically active agent as defined herein may be formulated together or separately. Desirably, a compound of the invention and a biologically active agent are formulated together for their simultaneous or near simultaneous administration. In another embodiment, two or more biologically active agents may be formulated together with a compound of the invention, or separately. Other examples include, but are not limited to, two or more compounds of the invention formulated together, wherein the compounds are formulated together with or without one or more biologically active agents.

The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include but are not limited to kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions.

The kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

Controlled Release Formulations

Each compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, can be formulated for controlled release (e.g., sustained or measured) administration, as described in U.S. Patent Application Publication Nos. 2003/0152637 and 2005/0025765, each incorporated herein by reference. For example, a compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, can be incorporated into a capsule or tablet that is administered to the patient.

Any pharmaceutically acceptable vehicle or formulation suitable for local application and/or injection into a site to be treated (e.g., a painful surgical incision, wound, or joint), that is able to provide a sustained release of compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, may be employed to provide for prolonged elimination or alleviation of inflammation, as needed. Controlled release formulations known in the art include specially coated pellets, polymer formulations or matrices for surgical insertion or as sustained release microparticles, e.g., microspheres or microcapsules, for implantation, insertion, infusion or injection, wherein the slow release of the active medicament is brought about through sustained or controlled diffusion out of the matrix and/or selective breakdown of the coating of the preparation or selective breakdown of a polymer matrix. Other formulations or vehicles for controlled, sustained or immediate delivery of an agent to a preferred localized site in a patient include, e.g., suspensions, emulsions, gels, liposomes and any other suitable art known delivery vehicle or formulation acceptable for subcutaneous or intramuscular administration.

A wide variety of biocompatible materials may be utilized as a controlled release carrier to provide the controlled release of a compound of the invention, alone or in combination with one or more biologically active agents, as described herein. Any pharmaceutically acceptable biocompatible polymer known to those skilled in the art may be utilized. It is preferred that the biocompatible controlled release material degrade in vivo within about one year, preferably within about 3 months, more preferably within about two months. More preferably, the controlled release material will degrade significantly within one to three months, with at least 50% of the material degrading into non-toxic residues, which are removed by the body, and 100% of the compound of the invention being released within a time period within about two weeks, preferably within about 2 days to about 7 days. A degradable controlled release material should preferably degrade by hydrolysis, either by surface erosion or bulk erosion, so that release is not only sustained but also provides desirable release rates. However, the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired reversible local anti-nociceptive effect over the desired time period.

Suitable biocompatible polymers can be utilized as the controlled release material. The polymeric material may comprise biocompatible, biodegradable polymers, and, in certain preferred embodiments, is preferably a copolymer of lactic and glycolic acid. Preferred controlled release materials which are useful in the formulations of the invention include the polyanhydrides, polyesters, co-polymers of lactic acid and glycolic acid (preferably wherein the weight ratio of lactic acid to glycolic acid is no more than 4:1 i.e., 80% or less lactic acid to 20% or more glycolic acid by weight) and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride. Examples of polyesters include polylactic acid, polyglycolic acid and polylactic acid-polyglycolic acid copolymers. Other useful polymers include protein polymers such as collagen, gelatin, fibrin and fibrinogen and polysaccharides such as hyaluronic acid.

The polymeric material may be prepared by any method known to those skilled in the art. For example, where the polymeric material is comprised of a copolymer of lactic and glycolic acid, this copolymer may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539, incorporated herein by reference. Alternatively, copolymers of lactic and glycolic acid may be prepared by any other procedure known to those skilled in the art. Other useful polymers include polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and polyorthoesters or mixtures or blends of any of these.

Pharmaceutically acceptable polyanhydrides which are useful in the present invention have a water-labile anhydride linkage. The rate of drug release can be controlled by the particular polyanhydride polymer utilized and its molecular weight. The polysaccharides may be poly-1,4-glucans, e.g., starch glycogen, amylose, amylopectin, and mixtures thereof. The biodegradable hydrophilic or hydrophobic polymer may be a water-soluble derivative of a poly-1,4-glucan, including hydrolyzed amylopectin, derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like. The polyanhydride polymer may be branched or linear.

Examples of polymers which are useful in the present invention include (in addition to homopolymers and copolymers of poly(lactic acid) and/or poly(glycolic acid)) poly[bis(p-carboxyphenoxy) propane anhydride] (PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides of oligomerized unsaturated aliphatic acids, polyanhydride polymers prepared from amino acids which are modified to include an additional carboxylic acid, aromatic polyanhydride compositions, and co-polymers of polyanhydrides with other substances, such as fatty acid terminated polyanhydrides, e.g., polyanhydrides polymerized from monomers of dimers and/or trimers of unsaturated fatty acids or unsaturated aliphatic acids. Polyanhydrides may be prepared in accordance with the methods set forth in U.S. Pat. No. 4,757,128, incorporated herein by reference. Polyorthoester polymers may be prepared, e.g., as set forth in U.S. Pat. No. 4,070,347, incorporated herein by reference. Polyphosphoesters may be prepared and used as set forth in U.S. Pat. Nos. 6,008,318, 6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907 and 5,194,581, each of which is incorporated herein by reference.

Proteinaceous polymers may also be used. Proteinaceous polymers and their soluble derivatives include gelation biodegradable synthetic polypeptides, elastin, alkylated collagen, alkylated elastin, and the like. Biodegradable synthetic polypeptides include poly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine, copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids. Suggested amino acids include L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.

In additional embodiments, the controlled release material, which in effect acts as a carrier for a compound of the invention, alone or in combination with one or more biologically active agents as described herein, can further include a bioadhesive polymer such as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or non-toxic lectins or the polymer itself may be bioadhesive, e.g., polyanhydride or polysaccharides such as chitosan.

In embodiments where the biodegradable polymer comprises a gel, one such useful polymer is a thermally gelling polymer, e.g., polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer such as Pluronic™ F127 from BASF Wyandotte. In such cases, the local anesthetic formulation may be injected via syringe as a free-flowing liquid, which gels rapidly above 300° C. (e.g., when injected into a patient). The gel system then releases a steady dose of a compound of the invention, alone or in combination with one or more biologically active agents as described herein, at the site of administration.

Dosage Forms for Oral Use

Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, taste masking agents (such as hydroxypropyl methylcellulose, hydroxypropyl cellulose), and the like.

One or more compounds of the invention and one or more biologically active agents, as defined herein, may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned. In one example, a compound of the invention is contained on the inside of the tablet, and the biologically active agent is on the outside of the tablet, such that a substantial portion of the biologically active agent is released prior to the release of the compound of the invention.

Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Formulations for oral administration to the mouth may also be provided as a mouthwash, an oral spray, oral rinse solution, oral ointment, or oral gel.

Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Generally, when administered to a human, the oral dosage of any of the compounds of the combination of the invention will depend on the nature of the compound, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day. Dosages up to 200 mg per day may be necessary.

Administration of each drug in a combination therapy, as described herein, can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases.

Parenteral Formulations

Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 g/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

Topical Formulations

The compositions of the invention, alone or in combination with one or more of the biologically active agents described herein, can also be adapted for topical use with a topical vehicle containing from between 0.0001% and 25% (w/w) or more of active ingredient(s).

In a preferred combination, the active ingredients are preferably each from between 0.0001% to 10% (w/w), more preferably from between 0.0005% to 4% (w/w) active agent. The topical formulation, including but not limited to a cream, gel, or ointment, can be applied one to four times daily, or as needed. Performing the methods described herein, the topical vehicle containing the composition of the invention, or a combination therapy containing a composition of the invention is preferably applied to the site of inflammation on the patient. For example, a cream may be applied to the hands of a patient suffering from arthritic fingers.

The compositions can be formulated using any dermatologically acceptable carrier. Exemplary carriers include a solid carrier, such as alumina, clay, microcrystalline cellulose, silica, or talc; and/or a liquid carrier, such as an alcohol, a glycol, or a water-alcohol/glycol blend. The therapeutic agents may also be administered in liposomal formulations that allow therapeutic agents to enter the skin. Such liposomal formulations are described in U.S. Pat. Nos. 5,169,637; 5,000,958; 5,049,388; 4,975,282; 5,194,266; 5,023,087; 5,688,525; 5,874,104; 5,409,704; 5,552,155; 5,356,633; 5,032,582; 4,994,213; 8,822,537, and PCT Publication No. WO 96/40061. Examples of other appropriate vehicles are described in U.S. Pat. Nos. 4,877,805, 8,822,537, and EP Publication No. 0586106A1. Suitable vehicles of the invention may also include mineral oil, petrolatum, polydecene, stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, or vegetable oil.

The composition can further include a skin penetrating enhancer, such as those described in “Percutaneous Penetration enhancers”, (eds. Smith E W and Maibach H I. CRC Press 1995). Exemplary skin penetrating enhancers include alkyl (N,N-disubstituted amino alkanoate) esters, such as dodecyl 2-(N,N dimethylamino) propionate (DDAIP), which is described in patents U.S. Pat. Nos. 6,083,996 and 6,118,020, which are both incorporated herein by reference; a water-dispersible acid polymer, such as a polyacrylic acid polymer, a carbomer (e.g., Carbopol™ or Carbopol 940P™, available from B. F. Goodrich Company (Akron, Ohio)), copolymers of polyacrylic acid (e.g., Pemulen™ from B. F. Goodrich Company or Polycarbophil™ from A. H. Robbins, Richmond, Va.; a polysaccharide gum, such as agar gum, alginate, carrageenan gum, ghatti gum, karaya gum, kadaya gum, rhamsan gum, xanthan gum, and galactomannan gum (e.g., guar gum, carob gum, and locust bean gum), as well as other gums known in the art (see for instance, Industrial Gums: Polysaccharides & Their Derivatives, Whistler R. L., BeMiller J. N. (eds.), 3rd Ed. Academic Press (1992) and Davidson, R. L., Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc., N.Y. (1980)); or combinations thereof.

Other suitable polymeric skin penetrating enhancers are cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose. Additionally, known transdermal penetrating enhancers can also be added, if desired. Illustrative are dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide (DEET), 1-dodecylazacycloheptane-2-one (AZONE™, a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate and other enhancers such as dioxolanes, cyclic ketones, and their derivatives and so on.

Also illustrative are a group of biodegradable absorption enhancers which are alkyl N,N-2-(disubstituted amino) alkanoates as described in U.S. Pat. Nos. 4,980,378 and 5,082,866, which are both incorporated herein by reference, including: tetradecyl (N,N-dimethylamino) acetate, dodecyl (N,N-dimethylamino) acetate, decyl (N,N-dimethylamino) acetate, octyl (N,N-dimethylamino) acetate, and dodecyl (N,N-diethylamino) acetate.

Particularly preferred skin penetrating enhancers include isopropyl myristate; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalanine amide of a medium chain fatty acid; dodecyl 2-(N,N-dimethylamino) propionate or salts thereof, such as its organic (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acid addition salts) and inorganic salts (e.g., acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfamic, picric, and lactic acid addition salts), as described in U.S. Pat. No. 6,118,020; and alkyl 2-(N,N-disubstituted amino)-alkanoates, as described in U.S. Pat. Nos. 4,980,378 and 5,082,866.

The skin penetrating enhancer in this composition by weight would be in the range of 0.5% to 10% (w/w). The most preferred range would be between 1.0% and 5% (w/w). In another embodiment, the skin penetrating enhancer comprises between 0.5%-1%, 1%-2%, 2%-3%, 3%-4%, or 4%-5%, (w/w) of the composition.

The compositions can be provided in any useful form. For example, the compositions of the invention may be formulated as solutions, emulsions (including microemulsions), suspensions, creams, ointments, foams, lotions, gels, powders, or other typical solid, semi-solid, or liquid compositions (e.g., topical sprays) used for application to the skin or other tissues where the compositions may be used. Such compositions may contain other ingredients typically used in such products, such as colorants, fragrances, thickeners (e.g., xanthan gum, a fatty acid, a fatty acid salt or ester, a fatty alcohol, a modified cellulose, a modified mineral material, KRISGEL100™, or a synthetic polymer), antimicrobials, solvents, surfactants, detergents, gelling agents, antioxidants, fillers, dyestuffs, viscosity-controlling agents, preservatives, humectants, emollients (e.g., natural or synthetic oils, hydrocarbon oils, waxes, or silicones), hydration agents, chelating agents, demulcents, solubilizing excipients, adjuvants, dispersants, skin penetrating enhancers, plasticizing agents, preservatives, stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers, moisturizers, astringents, deodorants, and optionally including anesthetics, anti-itch actives, botanical extracts, conditioning agents, darkening or lightening agents, glitter, humectants, mica, minerals, polyphenols, silicones or derivatives thereof, sunblocks, vitamins, and phytomedicinals.

The compositions can also include other like ingredients to provide additional benefits and improve the feel and/or appearance of the topical formulation. Specific classes of additives commonly use in these formulations include: isopropyl myristate, sorbic acid NF powder, polyethylene glycol, phosphatidylcholine (including mixtures of phosphatidylcholine, such as phospholipon G), KRISGEL100™ distilled water, sodium hydroxide, decyl methyl sulfoxide (as a skin penetrating enhancer), menthol crystals, lavender oil, butylated hydroxytoluene, ethyl diglycol reagent, and 95% percent (190 proof) ethanol.

Formulations for Ophthalmic Administration

The compounds of the invention can also be formulated with an ophthalmically acceptable carrier in sufficient concentration so as to deliver an effective amount of the active compound or compounds to the optic nerve site of the eye. Preferably, the ophthalmic, therapeutic solutions contain one or more of the active compounds in a concentration range of approximately 0.0001% to approximately 5% (weight by volume) and more preferably approximately 0.0005% to approximately 0.1% (weight by volume).

An ophthalmically acceptable carrier does not cause significant irritation to the eye and does not abrogate the pharmacological activity and properties of the charged sodium channel blockers.

Ophthalmically acceptable carriers are generally sterile, essentially free of foreign particles, and generally have a pH in the range of 5-8. Preferably, the pH is as close to the pH of tear fluid (7.4) as possible. Ophthalmically acceptable carriers are, for example, sterile isotonic solutions such as isotonic sodium chloride or boric acid solutions. Such carriers are typically aqueous solutions contain sodium chloride or boric acid. Also useful are phosphate buffered saline (PBS) solutions.

Various preservatives may be used in the ophthalmic preparation. Preferred preservatives include, but are not limited to, benzalkonium potassium, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Likewise, various preferred vehicles may be used in such ophthalmic preparation. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose and hydroxyethyl cellulose.

Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, etc., mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed. Ophthalmically acceptable antioxidants can also be include. Antioxidants include but are not limited to sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

Formulations for Nasal and Inhalation Administration

The pharmaceutical compositions of the invention can be formulated for nasal or intranasal administration. Formulations suitable for nasal administration, when the carrier is a solid, include a coarse powder having a particle size, for example, in the range of approximately to 500 microns which is administered by rapid inhalation through the nasal passage. When the carrier is a liquid, for example, a nasal spray or as nasal drops, one or more of the formulations can be admixed in an aqueous or oily solution and inhaled or sprayed into the nasal passage.

For administration by inhalation, the active ingredient can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount, Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of, for example, gelatin or blisters of, for example, laminated aluminum foil, for use in an inhaler or insufflator. Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di or ploy-saccharides (e.g. lactose or starch). Use of lactose is preferred. In one embodiment, each capsule or cartridge may contain between about 2 ug to about 100 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. In a preferred embodiment, each capsule or cartridge may contain between about 10 ug to about 50 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. In another embodiment, each capsule or cartridge may contain between about 20 ug to about 10 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. Alternatively, the compound of the invention may be delivered without excipients.

Suitably, the packaging/medicament dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), a multi-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI).

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain an aqueous medium, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient(s); a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Compositions formulated for nasal or inhalation administration may include one or more taste-masking agents such as flavoring agents, sweeteners, and other strategies, such as sucrose, dextrose, and lactose, carboxylic acids, menthol, amino acids or amino acid derivatives such as arginine, lysine, and monosodium glutamate, and/or synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, etc. and combinations thereof. These may include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, bay oil, anise oil, eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. Additional sweeteners include sucrose, dextrose, aspartame, acesulfame-K, sucralose and saccharin, organic acids (by non-limiting example citric acid and aspartic acid). Such flavors may be present at from about 0.05 to about 4 percent by weight, and may be present at lower or higher amounts as a factor of one or more of potency of the effect on flavor, solubility of the flavorant, effects of the flavorant on solubility or other physicochemical or pharmacokinetic properties of other formulation components, or other factors.

Indications

The compounds, compositions, methods, and kits of the invention can be used to treat pain, cough or itch associated with any of a number of conditions, including trigeminal trophic syndrome, erythromelalgia, back and neck pain, lower back pain, cancer pain, gynecological and labor pain, abdominal wall pain, chronic abdominal wall pain, fibromyalgia, allergic rhinitis, arthritis, rheumatoid arthritis, osteoarthritis, rheumatological pains, orthopedic pains, acute and post herpetic neuralgia and other neuropathic pains (including peripheral neuropathy), sickle cell crises, muscle pain, vulvodynia, rectal pain, Levator ani syndrome, proctalgia fugax, peri-anal pain, hemorrhoid pain, stomach pain, ulcers, inflammatory bowel disease, irritable bowel disease, irritable bowel syndrome, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urological pains, dental pain, burn pain, headaches, ophthalmic irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, dry eye syndrome (chronic ocular pain), complex regional pain syndrome, acute postoperative pain, postoperative pain, post-surgical ocular pain, and procedural pain (i.e., pain associated with injections, draining an abscess, surgery, dental procedures, ophthalmic procedures, ophthalmic irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, arthroscopies and use of other medical instrumentation, cosmetic surgical procedures, dermatological procedures, setting fractures, biopsies, and the like).

Since a subclass of nociceptors mediate itch sensation, the compounds, compositions, methods, and kits of the invention can also be used to treat itch in patients with conditions like pruritus (including, but not limited to, brachioradial, chronic idiopathic, genital/anal, notalgia paresthetica, and scalp), allergic dermatitis, atopic dermatitis, contact dermatitis, poison ivy, infections, parasites, insect bites, pregnancy, metabolic disorders, liver or renal failure, drug reactions, allergic reactions, eczema, hand eczema, genital and anal itch, hemorrhoid itch, and cancer.

Since a subclass of nociceptors can initiate aberrant cough reflexes, the compounds, compositions, methods, and kits of the invention can also be used to treat cough in patients with conditions like asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post viral cough, post-infection cough, chronic idiopathic cough and lung cancer.

The compounds, compositions, methods, and kits of the invention can also be used to treat neurogenic inflammation and neurogenic inflammatory disorders. Inflammation is a complex set of responses to harmful stimuli that results in localized redness, swelling, and pain. Inflammation can be innate or adaptive, the latter driven by antigens and is mediated by immune cells (immune-mediated inflammation). Neurogenic inflammation results from the efferent functions of pain-sensing neurons (nociceptors), wherein neuropeptides and other chemicals that are pro-inflammatory mediators are released from the peripheral terminals of the nociceptors when they are activated. This release process is mediated by calcium influx and exocytosis of peptide containing vesicles, and the pro-inflammatory neuropeptides include substance P, neurokinin A and B (collectively known as tachykinins), calcitonin gene-related peptide (CGRP), and vasoactive intestinal polypeptide (VIP).

The release of peripheral terminal chemicals stimulate a variety of inflammatory responses. First, the release of substance P can result in an increase in capillary permeability such that plasma proteins leak from the intravascular compartment into the extracellular space (plasma extravasation), causing edema. This can be detected as a wheal (a firm, elevated swelling of the skin) which is one component of a triad of inflammatory responses-wheal, red spot, and flare-known as the Lewis triple response. Second, the release of CGRP causes vasodilation, leading to increased blood flow. This can be detected as a flare, which is another component of the Lewis triple response.

Substance P also has a pro-inflammatory action on immune cells (e.g. macrophages, T-cells, mast cells, and dendritic cells) via their neurokinin-1 (NK1) receptor. This effect has been documented in allergic rhinitis, gastritis, and colitis, and represents an interface between the neurogenic and immune-mediated components of inflammation. Substance P released from one nociceptor may also act on NK1 receptors on neighboring nociceptors to sensitize or activate them, causing a spread of activation and afferent/efferent function. These efferent functions of nociceptors can be triggered by: 1) Direct activation of a nociceptor terminal by a peripheral adequate stimulus applied to the terminal (e.g. a pinch); 2) Indirect antidromic activation of a non-stimulated nociceptor terminal by the axon reflex, wherein action potential input from one terminal of a nociceptor, upon reaching a converging axonal branch point in the periphery, results in an action potential traveling from the branch point down to the peripheral terminal of a non-stimulated terminal; and 3) Activation as a result of activity in nociceptor central terminals in the CNS traveling to the periphery (e.g., primary afferent depolarization of central terminals produced by GABA can be sufficient to initiate action potentials traveling the “wrong way”).

Genomic analysis of lung resident ILC2 cells has revealed expression of receptors for several neuropeptides released by sensory neurons, including SP, CGRP and VIP, providing an opportunity for nociceptors to directly communicate with these cells. In particular, VIP is found to be expressed in NaVI.8+ nodose ganglion neurons, including lung afferents in OVA-exposed mice. Cultured nodose ganglion neurons stimulated with capsaicin or IL5 also released VIP while BALF from OVA-exposed mice contained elevated VIP compared to vehicle-challenged mice (Talbot et al., Neuron. 2015 Jul. 15; 87(2): 341-354). These data indicate that VIP is released in the inflamed lung and can be blocked by silencing neurons with charged sodium channel blockers of the present invention. In addition, when CD4+ T cells cultured under T_(H)2 skewing conditions were exposed to recombinant mouse VIP, the transcript levels of IL-13 and IL-5 increased, suggesting that VIP contributes to the competence of T_(H)2 cells to transcribe these type II regulatory cytokines.

Immune mediator release from immune cells can also activate nociceptors. Mast cells are found close to primary nociceptive neurons and contribute to nociceptor sensitization in a number of contexts. Injection of the secretagogue compound 48/80 promotes degranulation of mast cells in the dura and leads to excitation of meningeal nociceptors. Mast cell degranulation also contributes to the rapid onset of nerve growth factor-induced thermal hyperalgesia. Macrophages contribute to nociceptor sensitization by releasing several soluble mediators. Expression of the chemokine macrophage inflammatory protein-la (MIP-la) and its receptors CCR1 and CCR5 is increased in macrophages and Schwann cells after partial ligation of the sciatic nerve and contributes to the development of neuropathic pain. Lymphocytes contribute to the sensitization of peripheral nociceptors. T cells infiltrate the sciatic nerve and dorsal root ganglion (DRG) after nerve injury. Hyperalgesia and allodynia induced by nerve injury are markedly attenuated or abrogated in rodents lacking T cells and the immunosuppressant rapamycin attenuates neuropathic pain in rats, partly owing to an effect on T cells. Among the subsets of T cells, type 1 and 2 helper T cells (T_(H)1 and T_(H)2 cells) have been shown to have different roles in neuropathic pain. T_(H)1 cells facilitate neuropathic pain behavior by releasing proinflammatory cytokines (IL-2 and interferon-7 (IFNγ)), whereas T_(H)2 cells inhibit it by releasing anti-inflammatory cytokines (IL-4, IL-10 and IL-13). The complement system also has a role in inflammatory hyperalgesia and neuropathic pain. C5a, an anaphylatoxin, is an important effector of the complement cascade and upon binding to C5aR1 receptors on neutrophils it becomes a potent neutrophil attractant (Ren & Dubner, Nat. Med. 16:1267-1276 (2010)).

Bacterial infections have been shown to directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice (Chiu et al., Nature 501:52-57 (2013)). Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions. Data from Talbot et al., (Neuron. 2015 Jul. 15; 87(2): 341-354.) have also suggested that nociceptors are activated during exposure to allergens in sensitized animals.

In certain disorders, neurogenic inflammation contributes to the peripheral inflammation elicited by tissue injury, autoimmune disease, infection, and exposure to irritants in soft tissue, skin, the respiratory system, joints, the urogenital and GI tract, the liver, and the brain. Neurogenic inflammatory disorders include, but are not limited to, allergic inflammation, inflammatory bowel disease, interstitial cystitis, atopic dermatitis, asthma, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, psoriasis, rhinitis, rosacea, sunburn, pancreatitis, chronic cough, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, or chemical warfare agents, as described herein.

Assessment of Pain, Cough, Itch, and Neurogenic Inflammation

In order to measure the efficacy of any of the compounds, compositions, methods, and kits of the invention in the treatment of pain associated with musculoskeletal, immunoinflammatory and neuropathic disorders, a measurement index may be used. Indices that are useful include a visual analog scale (VAS), a Likert scale, categorical pain scales, descriptors, the Lequesne index, the WOMAC index, and the AUSCAN index, each of which is well known in the art. Such indices may be used to measure pain, itch, function, stiffness, or other variables.

A visual analog scale (VAS) provides a measure of a one-dimensional quantity. A VAS generally utilizes a representation of distance, such as a picture of a line with hash marks drawn at regular distance intervals, e.g., ten 1-cm intervals. For example, a patient can be asked to rank a sensation of pain or itch by choosing the spot on the line that best corresponds to the sensation of pain or itch, where one end of the line corresponds to “no pain” (score of 0 cm) or “no itch” and the other end of the line corresponds to “unbearable pain” or “unbearable itch” (score of 10 cm). This procedure provides a simple and rapid approach to obtaining quantitative information about how the patient is experiencing pain or itch. VAS scales and their use are described, e.g., in U.S. Pat. Nos. 6,709,406 and 6,432,937.

A Likert scale similarly provides a measure of a one-dimensional quantity. Generally, a Likert scale has discrete integer values ranging from a low value (e.g., 0, meaning no pain) to a high value (e.g., 7, meaning extreme pain). A patient experiencing pain is asked to choose a number between the low value and the high value to represent the degree of pain experienced. Likert scales and their use are described, e.g., in U.S. Pat. Nos. 6,623,040 and 6,766,319.

The Lequesne index and the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index assess pain, function, and stiffness in the knee and hip of OA patients using self-administered questionnaires. Both knee and hip are encompassed by the WOMAC, whereas there is one Lequesne questionnaire for the knee and a separate one for the hip. These questionnaires are useful because they contain more information content in comparison with VAS or Likert. Both the WOMAC index and the Lequesne index questionnaires have been extensively validated in OA, including in surgical settings (e.g., knee and hip arthroplasty). Their metric characteristics do not differ significantly.

The AUSCAN (Australian-Canadian hand arthritis) index employs a valid, reliable, and responsive patient self-reported questionnaire. In one instance, this questionnaire contains 15 questions within three dimensions (Pain, 5 questions; Stiffness, 1 question; and Physical function, 9 questions). An AUSCAN index may utilize, e.g., a Likert or a VAS scale.

Indices that are useful in the methods, compositions, and kits of the invention for the measurement of pain include the Pain Descriptor Scale (PDS), the Visual Analog Scale (VAS), the Verbal Descriptor Scales (VDS), the Numeric Pain Intensity Scale (NPIS), the Neuropathic Pain Scale (NPS), the Neuropathic Pain Symptom Inventory (NPSI), the Present Pain Inventory (PPI), the Geriatric Pain Measure (GPM), the McGill Pain Questionnaire (MPQ), mean pain intensity (Descriptor Differential Scale), numeric pain scale (NPS) global evaluation score (GES) the Short-Form McGill Pain Questionnaire, the Minnesota Multiphasic Personality Inventory, the Pain Profile and Multidimensional Pain Inventory, the Child Heath Questionnaire, and the Child Assessment Questionnaire.

Itch can be measured by subjective measures (VAS, Lickert, descriptors). Another approach is to measure scratch which is an objective correlate of itch using a vibration transducer or movement-sensitive meters.

Cough can be measured by standard questionnaires like the Leicester Cough Questionnaire as well as validated objective instruments to measure cough frequency (e.g. VitaloJAK).

EXAMPLES

The following examples are intended to illustrate the invention and are not intended to limit it.

Example 1—Compound Syntheses General Abbreviation Definitions

ACN acetonitrile aq. aqueous 6 chemical shift (ppm) DCM dichloromethane DMSO dimethyl sulfoxide ESI electrospray ionization Et₂O diethyl ether EtOAc ethyl acetate h hour MeOH methanol mHz megahertz MS mass spectrometry m/z mass to charge ratio NMR nuclear magnetic resounance Red-Al sodium bis (2-methoxyethoxy) aluminium hydride RT room temperature HSi(OEt)₃ triethoxysilane PMA phosphomolybdic acid THE tetrahydrofuran Ti(OiPr)₄ titanium(IV) isopropoxide TLC thin layer chromatography UV ultraviolet light

1. Synthesis of (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) triethylphosphonium bromide

Synthesis of Intermediate 2-bromo-N-(2,6-dimethylphenyl)acetamide

To a suspension of 2, 6-dimethylaniline (30.5 mL, 247.56 mmol, 1.0 eq) in water (300 mL) was added bromoacetyl bromide (23.8 mL, 272.31 mmol, 1.1 eq) at 10° C. The reaction mixture was maintained at pH 9-10 with 15% Na₂CO₃ (aq.) solution for 1 hour as the progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in hexane, visualization by UV). The reaction mixture was extracted with EtOAc (2×600 mL) and the combined organic extracts were washed with brine (200 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting crude product was triturated with Et₂O (2×200 mL) to afford 2-bromo-N-(2, 6-dimethylphenyl) acetamide (21 g) as a white solid. MS (ESI): m/z 244.02 [M+2]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (br s, 1H), 7.20-7.02 (m, 3H), 4.07 (s, 2H), 2.24 (s, 6H).

Synthesis of (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) triethylphosphonium bromide

To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl) acetamide (150 mg, 0.6195 mmol, 1.0 eq) in ACN (2 mL) was added 1M triethylphosphine in THE (2.478 ml, 2.478 mmol, 4 eq) at room temperature, and the resulting reaction mixture was stirred at 100° C. for 16 h in sealed tube as progress of the reaction was monitored by TLC (mobile phase 10% MeOH in DCM, visualization by UV). The mixture was concentrated under reduced pressure to afford a crude residue which was triturated with EtOAc (2×10 mL) to afford (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) triethylphosphonium bromide (0.12 g) as a white solid. MS (ESI): m/z 280.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.88 (s, 1H), 7.02-7.16 (m, 3H), 3.83 (d, J=14.03 Hz, 2H), 2.26-2.43 (m, 6H), 2.17 (s, 6H), 1.21 (dt, J=18.85, 7.67 Hz, 9H).

2. Synthesis of (1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl) triethylphosphonium

Synthesis of Intermediate 2-bromobutanoyl chloride

Thionyl chloride (150 mL) was added to 2-bromobutanoic acid (25 g, 149.7 mmol, 1.0 eq) at 0° C. and the resulting solution was subsequently stirred at 80° C. for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure to afford crude 2-bromobutanoyl chloride (27.7 g, 99.5%) as a brown residue which was taken to next step immediately without further purification. ¹H NMR (400 MHz, CDCl₃) δ 4.52-4.44 (m, 1H), 2.29-2.16 (m, 1H), 2.15-2.02 (m, 1H), 1.10 (t, J=7.3 Hz, 3H).

Synthesis of Intermediate 2-bromo-N-(2, 6-dimethylphenyl) butanamide

A solution of 2, 6-dimethylaniline (15 g, 121.18 mmol, 1.0 eq) and pyridine (15 mL, 189.6 mmol, 1.5 eq) in DCM (400 mL) was cooled in an ice bath to 0° C. To this mixture was slowly added a solution of 2-bromobutanoyl chloride (27.5 g, 148.6 mmol, 1.2 eq) in DCM (50 mL) and the resulting mixture was allowed to warm to room temperature while stirring for 2 h. The reaction solution was adjusted to pH 5 to 6 with 2 N HCl and extracted with DCM (2×200 mL). The combined organic extracts were washed with water (250 mL) and brine (200 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting crude product was triturated with n-pentane (150 mL) to afford 2-bromo-N-(2,6-dimethylphenyl)butanamide (30 g). MS (ESI): m/z 272.13 [M+2]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.69 (s, 1H), 7.15-7.02 (m, 3H), 4.51 (t, J=7.3 Hz, 1H), 2.22-2.04 (m, 7H), 2.03-1.91 (m, 1H), 0.98 (t, J=7.3 Hz, 3H).

Synthesis of (1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl) triethylphosphonium carbonate

To a solution of 2-bromo-N-(2,6-dimethylphenyl)butanamide (1 g, 3.70 mmol, 1.0 eq) in ACN (5 mL) was added 1 M triethylphosphine in THE (5.55 mL, 5.55 mmol, 1.5 eq) at room temperature, and the resulting reaction mixture was stirred at 100° C. for 24 h in a sealed tube as progress of the reaction was monitored by TLC (mobile phase 10% MeOH in DCM, visualization by UV). The reaction mixture was concentrated under reduced pressure and the crude residue was triturated with EtOAc (2×15 mL) to deliver 1.3 g product that was further purified by reverse phase preparative HPLC (column Xbridge C18 (30λ250) mm 5 u; mobile phase 10 mM ammonium bicarbonate in water; ACN gradient 0/15, 11.3/76, 11.4/99, 13/99, 13.1/15, 18/15; flow: 0.6 mL/min). Pure fractions were collected and lyophilized to afford (1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl) triethylphosphonium carbonate (0.017 g). MS (ESI): m/z 308.38 [M]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.02-11.58 (m, 1H), 6.89-7.24 (m, 3H), 3.96-4.28 (m, 1H), 2.31-2.46 (m, 6H), 2.20 (s, 6H), 1.81-2.01 (m, 2H), 1.03-1.33 (m, 12H).

3. Synthesis of 1-benzyl-1-(2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phosphepan-1-ium bromide

Synthesis of Intermediate 1-benzylphosphepane 1-oxide

To a stirred solution of diethyl benzyl phosphonate (25 g, 109.53 mmol, 1.0 eq) in THE (250 mL) was added sodium bis (2-methoxyethoxy) aluminium hydride (Red-Al, 3.6 M in toluene, 87.6 mL, 315.36 mmol, 2.87 eq) and 1,6-dibromohexane (16.85 mL, 109.52 mmol, 0.99 eq), and the reaction mixture was stirred at 70° C. for 48 h as progress of the reaction was monitored by TLC (mobile phase 10% MeOH in DCM, visualization by UV). The reaction mixture was quenched with 20 mL water and filtered through celite. The filtrate was concentrated under reduced pressure to afford crude product which was purified by column chromatography (silica gel 60-120 mesh (500 g); elution with MeOH in DCM using a 0%-5% gradient) to afford 1-benzylphosphepane 1-oxide as an off-white solid.

Synthesis of 1-benzyl-1-(2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phosphepan-1-ium bromide

To a stirred solution of 1-benzylphosphepane 1-oxide (0.5 g, 2.249 mmol, 1.0 eq) in THE (25 mL) was added HSi(OEt)₃ (4.15 mL, 22.48 mmol, 9.99 eq) and Ti(O-iPr)₄ (0.66 ml, 2.21 mmol, 0.98 eq). The reaction mixture was stirred at 80° C. for 24 h and then allowed to cool to room temperature. Next, a solution of 2-bromo-N-(2,6-dimethylphenyl) acetamide (0.599 g, 2.47 mmol, 1.098 eq) in THE (15 mL) was added and the resulting reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered and subsequently triturated with ethyl acetate (15 mL) and water (3×25 mL) to afford 1-benzyl-1-(2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phosphepan-1-ium bromide (150 mg). MS (ESI): m/z 368.47 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.86 (s, 1H), 7.31-7.53 (m, 5H), 7.01-7.21 (m, 3H), 3.92 (br d, J=16.14 Hz, 2H), 3.72 (br d, J=13.69 Hz, 2H), 2.38-2.50 (m, 4H), 2.18 (s, 6H), 1.65-2.01 (m, 4H), 1.59 (br s, 4H).

4. Synthesis of 1-benzyl-1-(2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phosphinan-1-ium bromide

Synthesis of Intermediate-benzylphosphinane 1-oxide

To a stirred solution of diethyl benzyl phosphonate (10 g, 43.815 mmol, 1.0 eq) in THE (100 mL) was added Red-Al (3.6 M in toluene, 24.34 mL, 87.624 mmol, 1.99 eq) at room temperature. After stirring for 10 min, 1,5-diiodopentane (8.474 mL, 56.948 mmol, 1.299 eq) was added and the solution was heated at 75° C. for 48 h as progress of the reaction was monitored by TLC (mobile phase 10% MeOH in DCM, visualization by UV). After cooling to room temperature, the reaction mixture was quenched with 20 mL water, filtered through celite and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to afford crude compound which was purified by phase flash chromatography (silica gel, elution with 5% of MeOH/DCM). Pure fractions were concentrated to afford product which was triturated with Et₂O (2×30 mL) to provide 1-benzylphosphinane 1-oxide as an off white solid. MS (ESI): m/z 208.11 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.10-7.48 (m, 5H), 3.17 (d, J=13.95 Hz, 2H), 1.91-2.11 (m, 2H), 1.63-1.89 (m, 6H), 1.45-1.62 (m, 2H).

Synthesis of 1-benzyl-1-(2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phosphinan-1-ium bromide

To a stirred solution of 1-benzylphosphinane 1-oxide (2.0 g, 9.604 mmol, 1.0 eq) in THE (20 mL) was added HSi(OEt)₃ (17.72 ml, 96.005 mmol, 9.99 eq) and Ti(O-iPr)₄ (2.873 ml, 9.704 mmol, 1.01 eq) at room temperature under argon, and the reaction mixture was heated to reflux for 16 h. Next, a solution of 2-bromo-N-(2, 6-dimethylphenyl) acetamide (3.487 g, 14.406 mmol, 1.5 eq) in THE (10 mL) was added drop wise and the reaction continued stirring at reflux for 6 h as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization by UV). The reaction mixture was allowed to cool to room temperature and the precipitated solid was filtered and washed with EtOAc (30 mL). This solid product was further stirred with H₂O (50 mL) for 15 min, filtered and dried. The resulting solid was triturated with EtOAc (50 mL) to afford 1-benzyl-1-(2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phosphinan-1-ium bromide (1.9 g) as an off white solid. MS (ESI): m/z 354 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.90 (s, 1H), 7.30-7.56 (m, 5H), 6.99-7.20 (m, 3H), 3.99 (d, J=16.09 Hz, 2H), 3.74 (d, J=13.71 Hz, 2H), 2.24-2.44 (m, 4H), 2.18 (s, 6H), 1.80-1.97 (m, 4H), 1.52 (br s, 2H).

5. Synthesis of 1-benzyl-1-(2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phospholan-1-ium bromide

Synthesis of Intermediate 1-benzylphospholane 1-oxide

To a stirred solution of diethyl benzylphosphonate (10 g, 43.815 mmol, 1.0 eq) in THE (100 mL) was added Red-Al (3.6 M in toluene, 25.307 mL, 91.105 mmol, 2.07 eq) and 1, 4-diiodobutane (7.48 mL, 56.71 mmol, 1.29 eq) at room temperature and the resulting mixture was stirred at 75° C. for 48 h as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization with ninhydrin). The reaction mixture was quenched with water and filtered through a celite pad that was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to afford crude product which was purified by flash chromatography (elution with 10%-15% MeOH/DCM gradient). The collected pure fractions were concentrated under reduced pressure to afford pure 1-benzylphospholane 1-oxide (1.5 g) as a white solid. MS (ESI): m/z 194.82 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.09-7.40 (m, 5H) 3.66-3.81 (m, 1H) 3.48-3.56 (m, 1H) 3.40 (s, 2H) 3.27 (d, J=14.82 Hz, 2H) 1.64-2.07 (m, 2H) 1.43-1.62 (m, 2H).

Synthesis of 1-benzyl-1-(2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phospholan-1-ium bromide

To a stirred solution of 1-benzylphospholane 1-oxide (0.5 g, 2.574 mmol, 1.0 eq) in THE (20 mL) was added HSi(OEt)₃ (4.75 ml, 25.73 mmol, 9.99 eq) and Ti(O-iPr)₄ (0.77 ml, 2.6 mmol, 1.01 eq) and the resulting mixture was stirred at 80° C. for 24 h. Next, a solution of 2-bromo-N-(2, 6-dimethylphenyl) acetamide (1.46 g, 6.03 mmol, 2.34 eq) in THE (10 mL) was added dropwise and the reaction was refluxed for 16 h as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization by UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude product which was triturated with MeOH/DCM (1:5 ratio, 12 mL), followed by EtOAc (15 mL) to deliver 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl) phospholan-1-ium bromide (0.055 g) as a white solid. Mass (ESI): m/z 340.49 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.95 (s, 1H) 7.32-7.52 (m, 5H) 7.04-7.16 (m, 3H) 3.86-4.02 (m, 4H) 2.28-2.44 (m, 4H) 2.18 (m, 6H) 1.79-2.00 (m, 2H) 1.42-1.69 (m, 2H).

6. Synthesis of 277 bis (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) diethyl phosphonium acetate

Synthesis of Intermediate Diethyl Phosphine Oxide

To a stirred solution of chlorodiethylphosphane (0.5 g, 4.014 mmol, 1.0 eq) in THE (15 mL) was added water (1.5 mL, degassed with argon) and the resulting mixture stirred for 24 h at room temperature as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization with PMA). The reaction mixture was concentrated under reduced pressure (150 psi) at low temperature (30° C.) to remove THE solvent, and then lyophilized to afford diethyl phosphine oxide (0.3 g) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.83-2.12 (m, 4H), 1.03-1.42 (m, 6H).

Synthesis of bis (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) diethyl phosphonium acetate

To a stirred solution of diethylphosphine oxide (0.2 g, 1.885 mmol, 1.0 eq) in THE (5 mL) was added HSi(OEt)₃ (3.479 mL, 18.84 mmol, 9.99 eq) and Ti (0-iPr)₄ (0.558 mL, 1.884 mmol, 0.99 eq) and the resulting mixture was heated for 4 h at 80° C. Next, 2-bromo-N-(2,6-dimethylphenyl)acetamide (0.913 g, 3.77 mmol, 2.0 eq) was added and the reaction continued stirring at 80° C. for 16 h as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization by UV). After cooling to room temperature, the reaction was concentrated under reduced pressure to afford crude product, which was purified by reverse phase Prep HPLC (column: Kromasil C18 (25×150) mm, 10 u; mobile phase (A): 10 mM ammonium acetate in H₂O: mobile phase (B): ACN (T/% B) 0/10, 9.8/67, 9.9/99, 11.8/99, 11.9/10, 14/10; flow: 25 ml/min). Pure fractions were lyophilized to afford bis (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) diethyl phosphonium acetate (0.018 g) as an off-white gummy solid. MS (ESI): m/z 413.49 [M]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.08-10.37 (m, 2H), 6.90-7.20 (m, 6H), 3.99 (br s, 4H), 2.15 (s, 12H), 1.63 (br s, 4H), 1.26 (br s, 6H).

7. Synthesis of 278 tri-n-butyl (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) phosphonium bromide

To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl) acetamide (200 mg, 0.826 mmol, 1.0 eq) in toluene (8 mL) was added tributylphosphine (184 mg, 0.909 mmol, 1.1 eq) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 16 h as progress was monitored by TLC (10% MeOH in DCM, visualization by UV). The reaction was concentrated under reduced pressure to afford crude product which was triturated with Et₂O (10 mL), pentane (10 mL) and EtOAc (10 mL) to afford tributyl (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl)phosphonium bromide (0.130 g) as a white solid. MS (ESI): m/z 364.52 [M]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.84 (s, 1H), 6.98-7.19 (m, 3H), 3.81 (d, J=13.89 Hz, 2 H), 2.24-2.36 (m, 6H), 2.16 (s, 6H), 1.48-1.63 (m, 6H), 1.31-1.49 (m, 6H), 0.92 (t, J=7.25 Hz, 9H).

8. Synthesis of 279 (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) triphenylphosphonium formate

To a stirred solution of 2, 6-dimethylaniline (0.500 g, 4.126 mmol, 1 eq) in ethanol (20 mL) was added (2-ethoxy-2-oxoethyl) triphenylphosphonium bromide (2.656 g, 6.186 mmol, 1.49 eq; Combi-Blocks, San Diego, Calif., catalogue number OR-8778) and the mixture was heated to 80° C. for 48 h as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization by UV). The reaction mixture was cooled to room temperature, diluted with DCM (60 mL) and washed with water (3×50 mL). The organic extract was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford crude product which was purified by flash chromatography (silica gel, elution with 5% MeOH in DCM) to afford 1 g of product which was further purified by reverse phase HPLC (column: Kromasil C18 (25λ150) mm 10 u, 10 mM mobile phase (A):ammonium bicarbonate in H₂O; mobile phase (B): ACN; (T/% B) 0/30, 9.3/69, 9.4/99, 12/99, 12.1/30, 13/30, flow: 25 mL/min). Pure fractions collected and lyophilized to afford 500 mg product 500 mg with LCMS purity of 88%. This product further purified by HPLC (column: X-Select C18 (19×250) mm 5 u, 0.1% formic acid in H₂O: ACN using a gradient method of 0:10, 6.8:56, 6.9:99, 10:99, 10.1:10, 12:10, flow: 18 mL/min). The pure fractions were collected and lyophilized to afford (2-((2, 6-dimethylphenyl) amino)-2-oxoethyl) triphenylphosphoniumformate (0.120 g) as an off white solid. MS (ESI): m/z 424.44 [M]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.38-10.84 (m, 1H) 8.44 (s, 1H) 7.57-8.07 (m, 15H) 6.90-7.11 (m, 3H) 5.17-5.65 (m, 2H) 1.96 (br s, 6H). Analytical data enclosed.

9. Synthesis of (1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl) triphenylphosphonium formate

Synthesis of Intermediate (1-ethoxy-1-oxobutan-2-yl) triphenyl phosphonium bromide

To a stirred solution of triphenyl phosphine (5 g, 19.06 mmol, 1 eq) in H₂O (20 mL) was added ethyl-2-bromobutyrate (4.462 g, 22.875 mmol, 1.2 eq) and the reaction was heated to 100° C. for 16 h as progress was monitored by TLC. (10% MeOH in DCM, visualization by UV). The reaction mixture was cooled to room temperature and extracted with DCM (3×20 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford crude product which was triturated with EtOAc (50 mL) to afford (1-ethoxy-1-oxobutan-2-yl) triphenyl phosphonium bromide (5.0 g) as a white solid. MS (ESI): m/z 377.41 [M]⁺. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.7-8.0 (m, 15H), 8.47 (s, 1H), 5.4 (t, 1H), 4.12 (q, 2H), 2.0 (m, 1H), 1.8 (m, 1H), 1.1 (t, 3H), 0.8 (t, 3H).

Synthesis of (1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl) triphenylphosphonium formate

To a stirred solution of (1-ethoxy-1-oxobutan-2-yl) triphenylphosphonium bromide (3.0 g, 6.559 mmol, 1 eq) in ethanol (60 mL) was added 2, 6-dimethylaniline (1.192 g, 9.836 mmol, 1.49 eq) at room temperature and the mixture was heated to 100° C. for 14 days in a sealed tube as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization by UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude product which was purified by reverse phase HPLC (column: X-select phenyl hexyl (150*19) mm, 5 u; mobile phase (A): 0.1% formic acid in water, mobile phase (B): acetonitrile; method (T/% B): 0/10, 2/10, 10/40, 14/50, 14.2/98, 17/98, 17.2/10, 20/10, Flow: 14 ml/min, ambient temperature). Pure fractions were collected and lyophilized to afford (1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl) triphenyl phosphonium formate (0.10 g) as a white solid. MS (ESI): m/z 452.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.52 (s, 1H), 8.47 (s, 1H), 7.82-8.08 (m, 9H), 7.76 (td, J=7.72, 3.52 Hz, 6H), 6.91-7.09 (m, 3H), 5.94 (br t, J=10.55 Hz, 1H), 1.59-2.23 (m, 8H), 1.24 (t, J=7.27 Hz, 3H).

10. Synthesis of 1-benzyl-1-(1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl)phosphinan-1-ium formate

Synthesis of Intermediate 1-benzyl-1-(1-ethoxy-1-oxobutan-2-yl) phosphinan-1-ium bromide

To a stirred solution of 1-benzylphosphinane 1-oxide (0.5 g, 2.401 mmol, 1.0 eq) in THE (10 mL) was added HSi(OEt)₃ (4.431 mL, 24 mmol, 9.99 eq) and Ti(O-iPr)₄ (0.718 mL, 2.425 mmol, 1.0 eq) and the reaction was stirred at 80° C. for 24 h. Next, ethyl 2-bromobutanoate (0.871 g, 4.465 mmol, 1.85 eq) was added and the reaction was refluxed for 16 as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization by UV). The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford crude product which was triturated with EtOAc (10 mL) to afford 1-benzyl-1-(1-ethoxy-1-oxobutan-2-yl) phosphinan-1-ium bromide (0.7 g) as a brown gum. MS (ESI): m/z 307.32 [M]⁺.

Synthesis of Intermediate 1-benzyl-1-(1-carboxypropyl) phosphinan-1-ium formate

A stirred solution of 1-benzyl-1-(1-ethoxy-1-oxobutan-2-yl) phosphinan-1-ium bromide (0.65 g, 1.678 mmol, 1.0 eq) in concentrated HCl (10 mL) was heated at 100° C. for 16 h as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization by UV). The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford crude product which was purified by reverse phase HPLC (column: X Select C18 (19*250) 5 u; mobile phase (A): 0.1% formic acid, mobile phase (B): 100% ACN, method (T/% B): 0/10, 2/10, 5/50, 20/50, 20.50/100, 22/100, 22.50/10, 25/10, flow: 18 mL/min). Pure fractions were concentrated under reduced pressure to afford 1-benzyl-1-(1-carboxypropyl) phosphinan-1-iumformate (0.15 g) as a colorless gum. Mass (ESI): m/z 279.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.46-14.57 (m, 1H), 7.24-7.54 (m, 5H), 3.84-4.10 (m, 2H), 3.48-3.62 (m, 1H), 2.20-2.39 (m, 4H), 1.83-2.02 (m, 2H), 1.58-1.84 (m, 4H), 1.34-1.58 (m, 2H), 0.98 (t, J=7.19 Hz, 3H).

Synthesis of 1-benzyl-1-(1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl) phosphinan-1-ium formate

To a solution of 1-benzyl-1-(1-carboxypropyl)phosphinan-1-ium formate (0.08 g, 0.2466 mmol, 1.0 eq) in ACN (2 mL) was added 2,6-dimethylaniline (0.0448 g, 0.369 mmol, 1.49 eq) and PCl₃ (0.3 ml, 3.429 mmol, 13.9 eq) and the mixture was heated in a microwave reactor (CEM Corporation, Matthews, N.C.) at 120° C. for 2 h as progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization by UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude product which was purified by reverse phase HPLC (column: X select Phenyl hexyle (150*19) mm, 5 u; mobile phase (A): 0.1% formic acid, mobile phase (B): ACN; method (T/% B): 0/10, 2/10, 10/50, 13/50, 13.2/98, 16/98, 16.2/10, 20/98; flow: 13 ml/min; ambient column temperature). The pure fractions were lyophilized to afford 1-benzyl-1-(1-((2, 6-dimethylphenyl) amino)-1-oxobutan-2-yl) phosphinan-1-ium formate as an off-white gum. Mass (ESI): m/z 282 [M]*. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.03 (s, 1H) 8.47 (s, 1H) 7.28-7.55 (m, 5H) 6.98-7.20 (m, 3H) 3.91-4.23 (m, 3H) 2.27-2.44 (m, 3H) 2.20 (s, 7H) 1.61-2.10 (m, 6H) 1.45 (br d, J=4.17 Hz, 2H) 1.10 (t, J=7.15 Hz, 3H).

Synthesis of Intermediate ethyl 2-amino-3-chlorobenzoate

Sulphuric acid (2 mL) was added drop wise to a stirred solution of 2-amino-3-chlorobenzoic acid (29.14 mmol, 1.0 eq) in ethanol (50 mL) and the reaction mixture was heated at 80° C. for 48 h. The reaction was cooled to room temperature and concentrated under reduced pressure to afford a crude residue which was diluted with ice water (300 mL) and extracted with EtOAc (3×300 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product which was purified by flash chromatography (5%-10% of EtOAc/Pet ether gradient). The pure fractions were combined and concentrated to afford 2-amino-3-chlorobenzoate (2.7 g) as a colourless gum. Mass (ESI): m/z 200.08[M+H]+ 0.1H NMR (400 MHz, CDCl₃) δ ppm 7.83-7.81 (m, 1H), 7.40-7.38 (m, 1H), 6.57 (t, 1H), 6.26 (br s, 2H), 4.36-4.31 (m, 2H), 1.38 (t, 3H).

Synthesis of Intermediate ethyl 2-amino-3-ethylbenzoate

To a stirred solution of 2-amino-3-bromobenzoic acid (10 g, 46.3 mmol) in DMF (100 mL) was added Cs2CO3 (45.25 g, 138.9 mmol) and ethyl iodide (14.4 g, 92.6 mmol) at room temperature. The resulting reaction mixture was stirred for 16 h as progress of the reaction was monitored by TLC (20% EtOAc in pet ether, visualization by UV). The reaction mixture was diluted with ice water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford ethyl 2-amino-3-bromobenzoate (8.5 g) as a pale brown solid that was used without further purification (MS (ESI): m/z 244.08 [M+H]⁺; 1H NMR (400 MHz, CDCl3) δ ppm 7.88-7.85 (m, 1H), 7.58-7.55 (m, 1H), 6.55-6.49 (m, 1H), 6.34 (br s, 2H), 4.34 (q, 2H), 1.38 (t, 3H). A stirred solution of ethyl 2-amino-3-bromobenzoate (5.5 g, 22.5 mmol) in DMF (100 mL) and H2O (10 mL) was treated with 4, 4, 5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolane (5.2 g, 33.8 mmol) and K2CO3 (9.3 g, 67.6 mmol) at room temperature and degassed with Argon for 15 min. The resulting reaction mixture was then treated with Pd(dppf)Cl2.DCM (0.92 g, 1.1 mmol) and stirred at 110° C. for 16 h as progress of the reaction was monitored by TLC (30% EtOAc in pet ether, visualization by UV). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts washed with water (2×50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product which was purified by flash chromatography (5%-10% of EtOAc in Pet ether). Pure fractions were combined and concentrated under reduced pressure to afford ethyl 2-amino-3-vinylbenzoate (3.5 g) as a pale red semi solid (MS (ESI): m/z 192.12 [M+H]⁺; 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (d, 1H), 7.38 (d, 1H), 6.77-6.70 (m, 1H), 6.66-6.62 (m, 1H), 5.97 (br s, 2H), 5.62 (d, 1H), 5.37 (d, 1H), 4.33 (q, 2H), 1.37 (t, 3H). To a stirred solution of ethyl 2-amino-3-vinylbenzoate (3.5 g, 18.3 mmol) in EtOAc (30 mL) was added 10% Pd/C (1.5 g) at room temperature. The resulting reaction mixture was stirred for 16 h at room temperature under H2 gas (balloon pressure) as progress of the reaction was monitored by TLC (0% EtOAc/Pet ether, Visualization by UV). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford ethyl 2-amino-3-ethylbenzoate (3 g) as brown semi solid (MS (ESI): m/z 194.08 [M+H]⁺).

Synthesis of Intermediate ethyl 2-amino-3-methoxybenzoate

To a stirred solution of 2-amino-3-methoxybenzoic acid (4 g, 23.9 mmol) in DCM (40 mL) was added SOCl2 (8.67 mL, 119.6 mmol) and the reaction mixture was stirred at 50° C. for 3 hours as progress of the reaction was monitored by TLC (30% EtOAc-pet-ether, visualization by UV). Ethanol (12 mL) was added drop wise to the reaction at 0° C. and the resulting mixture was stirred at 50° C. for 3 h. The reaction was then quenched with saturated NaHCO₃ solution and extracted with DCM (2×150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na₂SO4 and concentrated under reduced pressure to afford crude product which was purified by flash chromatography (10% EtOAc in pet-ether). Pure fractions were combined and concentrated to afford ethyl 2-amino-3-methoxybenzoate (1.5 g) as a yellow solid (Mass (ESI): m/z 196.07 [M+H]⁺; 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (dd, 1H), 6.84 (dd, 1H), 6.57 (t, 1H), 5.99 (s, 2H), 4.35-4.30 (m, 2H), 3.86 (s, 3H), 1.39-1.33 (m, 3H)).

Synthesis of Intermediate ethyl 2-amino-3-ethoxybenzoate

To a stirred solution of 3-hydroxy-2-nitrobenzoic acid (4 g, 21.84 mmol) and potassium carbonate (9.05 g, 65.52 mmol) in DMF (45 mL) was added ethyl iodide (6.81 g, 43.68 mmol) at 0° C. and the resulting reaction mixture was stirred at 60° C. for 16 hours as progress of the reaction was monitored by TLC (50% EtOAc in Pet ether, visualization by UV). The reaction mixture was cooled to room temperature, diluted with ice cold water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-ethoxy-2-nitrobenzoate (4.5 g) as a pale yellow gummy solid (1H NMR (400 MHz, CDCl₃) δ ppm 7.59-7.56 (m, 1H), 7.46 (t, 1H), 7.23-7.20 (m, 1H), 4.38-4.32 (m, 2H), 4.18-4.13 (m, 2H), 1.43-1.36 (m, 6H). A solution of ethyl 3-ethoxy-2-nitrobenzoate (4.5 g) in ethanol (200 mL) was treated with 10% Pd/C (1 g) at room temperature. The resulting reaction mixture was stirred under H2 atmosphere (Balloon pressure) for 16 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford ethyl 2-amino-3-ethoxybenzoate (3.1 g) as a pale yellow gummy (Mass (ESI): m/z 210.10 [M+H]⁺; 1H NMR (400 MHz, CDCl3) δ ppm 7.49-7.46 (m, 1H), 6.83 (d, 1H), 6.57-6.52 (m, 1H), 6.01 (br s, 2H), 4.36-4.29 (m, 2H), 4.10-4.03 (m, 2H), 1.47-1.35 (m, 6H).

Synthesis of Intermediate methyl 2-amino-3-cyanobenzoate

A stirred solution of methyl 2-amino-3-bromobenzoate (2.5 g, 10.9 mmol) and Zinc cyanide (2.5 g, 21.7 mmol) in DMF (20 mL) was treated with Tetrakis(triphenylphosphine)palladium(0) (627.5 mg, 0.54 mmol, 0.05 eq) at room temperature, and then degassed with Argon gas for 20 minutes. The resulting reaction mixture was heated at 80° C. for 16 h as progress of the reaction was monitored by TLC (5% EtOAc in pet ether, visualisation by UV). The reaction mixture was diluted with water (30 mL) and extracted with Ethyl acetate (2×100 mL). The organic extracts were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product which was purified by flash chromatography (2% EtOAc in pet ether) to afford methyl 2-amino-3-cyanobenzoate (750 mg) as a solid (Mass (ESI): m/z 177.08 [M+H]+ 0.1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.02 (m, 1H), 7.79-7.75 (m, 1H), 7.16 (br s, 2H), 6.71 (t, 1H), 3.90 (s, 3H).

Table A lists additional representative examples of the invention prepared from 1-benzyl-1-(1-carboxypropyl) phosphinan-1-ium formate and the corresponding aniline by employing methods described for Compound-10.

TABLE A Compound Structure MS (ESI): m/z 11

426.2 [M]⁺ 12

437.1 [M]⁺

Table B lists additional representative examples of the invention prepared from bromoacetyl bromide, 1-benzylphosphinane 1-oxide and the appropriate aniline by employing methods described for Compound-4. Compounds listed in table B were triturated with EtOAc or purified by reverse phase HPLC.

TABLE B Com- MS pound Structure (ESI): m/z 13

412.2 [M]⁺ 14

440.3 [M]⁺ 15

416.1 [M]⁺ 16

398.2 [M]⁺ 17

432.1 [M]⁺ 18

428.2 [M]⁺ 19

426.2 [M]⁺ 20

442.2 [M]⁺ Table C lists additional representative examples of the invention prepared from bromoacetyl bromide, methyl 2-amino-3-methylbenzoate and the appropriate trialkylphosphine by employing methods described for Compound-7.

TABLE C Compound Structure MS (ESI): m/z 21

324.2 [M]⁺ 22

408.3 [M]⁺

Table D lists an additional representative example of the invention prepared from (2-ethoxy-2-oxoethyl) triphenylphosphonium bromide and methyl 2-amino-3-methylbenzoate by employing methods described for Compound-8.

TABLE D Compound Structure MS (ESI): m/z 23

468.1 [M]⁺

Example 2—Inhibition of Nav1.7 Current

Representative compounds of the invention were synthesized according to the described methods and tested for the ability to inhibit voltage-gated sodium channels.

Cell Culture

NaV1.7 was expressed upon induction with tetracycline. Cells were cultured in DMEM containing 10% dialyzed Fetal Bovine Serum (VWR, Radnor, Pa.), 1% Glutamax (VWR, Radnor, Pa.), 1% Penicillin-Streptomycin (VWR, Radnor, Pa.), 100 mg/L Hygromycin (Thermo Fisher Scientific, Waltham, Mass. and 5 mg/L Blasticidin (Alfa Aesar, Haverhill, Mass.). Cells were grown and maintained at 37° C. in a humidified environment containing 10% CO₂ in air. Cells were detached from the culture flask for passage and harvested using 0.05% Trypsin-EDTA (Thermo Fisher Scientific, Waltham, Mass.). To induce NaV1.7, cells were induced with tetracycline (0.1-1 μg/mL, IBI Scientific, Peosta, Iowa) the day before recording and plated onto 24-well plates. Cells were washed with DPBS (VWR, Radnor, Pa.), trypsinized and then triturated five times in 10 mL of growth media to break apart cell aggregates. For one 24-well plate, 2 mL of cell suspension was mixed with 23 mL of fresh growth media and 0.1-1 μg/mL tetracycline added. 1 ml of mixed media with cells was then added to each well of a 24-well plate, with a 12 mm coverslip already placed in the bottom of the well. Cells were then incubated in 37° C. and 10% CO₂ overnight.

Patch Clamp Solutions & Drugs

The intracellular solution contained the following (in mM) CsCl 135, NaCl 10, EGTA 10, HEPES 10, MgCl₂2, adjusted to pH 7.2 with CsOH. The external solution was a normal Ringer solution containing (in mM) NaCl 155, HEPES 10, glucose 10, KCl 3.5, CaCl₂ 1.5, MgCl₂ 1 adjusted to pH 7.4 with NaOH. CsCl is from Alfa Aesar, Haverhill, Mass. All other chemicals are from Sigma-Aldrich, St. Louis, Mo. In order to test the degree of internal block by test compounds the compounds were dissolved in internal solution at the indicated test concentration. In control experiments the internal solution did not contain any compound. In order to test the degree of external block by test compounds the compounds were dissolved in external solution at the indicated test concentration.

Whole Cell Patch Clamp Protocol

18-24 hours after cells were induced with tetracycline, coverslips were placed into a chamber filled with Normal Ringer solution at room temperature and the chamber placed on a microscope. Pipettes were pulled from borosilicate glass on a P97 puller (Sutter Instrument, Novato, Calif.) and polished with a MF-830 Microforge (Narishige International USA, Inc, Amityville, N.Y.) to have a resistance of 1.5-2.5 MΩ when filled with CsCl internal solution at room temperature. Healthy cells (those that are round and translucent with no visible blemishes) were chosen for seal formation. A seal was formed between the pipette and the cell, and a brief pulse of suction was used to “break in” and establish the whole-cell configuration. The membrane potential was held at −100 mV before the voltage protocol began. Only cells with series resistance between 1.5-5 MΩ were retained for analysis. The voltage protocol was as follows: Cells were held at −100 mV for 12 ms followed by a hyperpolarizing step to −105 mV for 12 ms to monitor the leak. Cells were then stepped back to −100 mV for 40 ms. Cells were then depolarized to −20 mV for 10 ms and then returned to −100 mV for 26 ms (The FIGURE).

Internal Block by Test Compounds

Once the recording was started, the voltage protocol was run at 30 second intervals for 5 minutes to get a stable baseline. This was followed by four 30-second periods of 5 Hz stimulation of the same voltage protocol separated by 1 minute of rest which was then followed by 0.33 Hz stimulation after the last train. Currents were recorded using PatchMaster software with Heka EPC10 (HEKA Electronics, Lambrecht, Germany). Only cells with inward current amplitudes at −20 mV between 400 pA and 4 nA were accepted. In addition, cells having leak currents greater than 10% of their current amplitudes were discarded.

Data Analysis: Internal Block

The data was plotted using the Patchmaster software (HEKA Electronics, Lambrecht, Germany) and analyzed by plotting the minimum current during the voltage step to −20 mV (peak inward current) as a function of time. In order to determine the degree of rundown over the course of an experiment, the average peak inward current amplitude (2-3 points) before 5 Hz stimulation was designated as the baseline (I_(baseline)). The average peak inward current during the last 2 second of the last 5 Hz train was measured (I_(test)). The control fraction current remaining was calculated by dividing I_(test) by I_(baseline). On each recording day three cells were tested with control internal solution and the average fraction of current remaining calculated (Ctrl fraction current).

To determine the % block produced by test compounds applied internally the following was done. The average peak inward current amplitude (2-3 points) before 5 Hz stimulation was designated as 0% block (I_(0% block)). To correct for the current change under control conditions, I_(0% block) was multiplied by the average Ctrl fraction current remaining to get the corrected 0% block current. The average peak inward current during the last 2 seconds of the last 5 Hz train was designated as the unblocked current (I_(unblocked)). The % block was calculated using the following equation: (1−I_(unblocked)/(I_(0% block)*Ctrl fraction current remaining)×100).

Representative examples of the invention were tested for intracellular inhibition of NaV 1.7. Activity Range is % inhibition at 10 μM test concentration: “++++” (>95%), “+++” 95-70%, “++” (70-40%) or “+” (<40%). The results are presented below:

Nav1.7 Intracellular Compound Inhibition 1 +++ 2 ++ 3 ++++ 4 ++++ 5 +++ 6 +++ 7 ++++ 8 ++++ 9 ++++ 10 ++++

Representative examples of the invention were tested for intracellular inhibition of NaV 1.7. Activity Range is % inhibition at 3 μM test concentration: “++++” (>90%), “+++” 90-70%, “++” (70-40%) or “+” (<40%). The results are presented below:

Nav1.7 Intracellular Nav1.7 Intracellular Compound Inhibition Compound Inhibition 11 +++ 12 +++ 13 ++++ 14 ++ 15 +++ 16 +++ 17 ++++ 18 ++ 19 +++ 20 ++++ 21 + 22 +++ 23 +

External Block by Test Compounds

Once the recording was started, the voltage protocol was run at 30 second intervals for 5 minutes to get a stable baseline. This is followed by 5 Hz stimulation of the same voltage protocol run until the end of experiment. The test compound is added during the 5 Hz stimulation train making sure to wait until the cell shows stable current rundown rate before addition of the compound. The test compound is added for 5 minutes before washing out with normal Ringer's solution. Currents were recorded using PatchMaster software with Heka EPC10 (HEKA Electronics, Lambrecht, Germany). Only cells with inward current amplitudes at −20 mV between 400 pA and 4 nA were accepted. In addition, cells having leak currents greater than 10% of their current amplitudes were discarded.

Data Analysis: External Block

The data was plotted using the Patchmaster software (HEKA Electronics, Lambrecht, Germany) and analyzed by plotting the minimum current during the voltage step to −20 mV (peak inward current) as a function of time. To determine the % block produced by test compounds applied externally the following was done. After the stable current rundown rate was established during the 5 Hz stimulation train, the Rate_(rundown) was calculated by dividing the change in peak current amplitude by time. The average peak inward current amplitude (2-3 seconds) before addition of compound was used to determine 0% block (I_(0% block)). To correct for the rundown, I_(0% block) is subtracted by the (Rate_(rundown)*5 min) to get the corrected 0% block current. The average peak inward current during the last 2-3 seconds of the 5 minutes of compound application time before washing is the unblocked current (I_(unblocked)). The % block was then calculated using the following equation: Fraction current block=1−I_(unblocked)/(I_(0% block)−Rate_(rundown)*5 min).

Representative examples of the invention were tested for extracellular inhibition of NaV 1.7. Activity Range is % inhibition at the indicated test concentration: “++++” (>90%), “+++” 90-70%, “++” (70-40%) or “+” (<40%). The results are presented below:

Test Nav1.7 Extracellular Compound Concentration Inhibition 1 1,000 μM + 3 10 μM ++ 4 10 μM ++ 5 10 μM + 8 3 μM ++ 10 3 μM ++ 13 3 μM ++ 15 3 μM + 17 3 μM ++ 19 10 μM ++ 20 3 μM +

Example 3—Membrane Permeability

The PAMPA assay (pION, Inc., Woburn Mass.) was used to determine the ability of compounds of the invention to cross an artificial lipid membrane by passive diffusion. Test compounds were dissolved in DMSO (10 mM) and diluted 200-fold in buffer (pION Inc., pH 7.4) to provide 50 uM stock solutions. Buffer (150 μL) was added to a UV blank plate and stock solutions (150 μL) were transferred to a UV reference plate. The blank and reference spectrum were read using a spectrophotometer. Stock solutions (200 μL) were added to the donor plate of the PAMPA sandwich plate and an accept plate painted with GIT lipid (pION Inc, 5 μL) was placed on top. Buffer (200 μL) was added to the acceptor plate and the PAMPA sandwich plate was incubated for 4 hours. Aliquots (150 μL) from the acceptor plate were added to a UV plate and read as acceptor spectrum. Aliquots (150 μL) of the donor solutions were added to a UV analysis plate and read as donor spectrum. The permeability coefficient of test compounds was calculated using PAMPA Explorer™ software (version 3.5.0.4) based on the AUC of the reference plate, the donor plate, and the acceptor plate.

The PAMPA permeability results (10⁻⁶ cm/s) of representative compounds are reported as “+” (<0.1 10⁻⁶ cm/s), “++” (0.1-2.0 10⁻⁶ cm/s), “+++” (2.0-10.010⁻⁶ cm/s) or “++++” (>10.0 10⁻⁶ cm/s).

Compound PAMPA (10⁻⁶ cm/s) 1 + 2 ++++ 3 + 4 ++ 5 ++ 6 + 7 +++ 8 + 9 +++ 10 + 11 + 13 + 14 + 15 + 17 ++++ 19 + 20 + 21 + 22 + 23 +

The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. It will also be understood that none of the embodiments described herein are mutually exclusive and may be combined in various ways without departing from the scope of the invention encompassed by the appended claims. 

1. A compound represented by Formula (I)

wherein Y⁻ is a pharmaceutically acceptable anion; R^(A), R^(B), and R^(C) are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR^(I), NR^(J)R^(K), NR^(L)C(O)R^(M), CN, S(O)R^(N), S(O)₂R^(N), SO₂R^(O)R^(P), SO₂NR^(Q)R^(R), SO₃R^(S), CO₂R^(T), C(O)R^(U), and C(O)NR^(V)R^(W); each of R^(I), R^(J), R^(K), R^(L), R^(M), R^(N), R^(O), R^(P), R^(Q), R^(R), R^(S), R^(T), R^(U), R^(V), and R^(W) is independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; X¹ is selected from —CR^(X)R^(Y)—, —NR^(Z)C(O)—, —NR^(Z)C(O)CR^(X)R^(Y)—, —OC(O)—, —SC(O)—, —C(O)NR^(1A)—, —C(O)O—, —C(O)—, —(O)CS—, —NR^(1A)S(O)—, —S(O)NR^(1A)—, —NR^(1A)C(O)NR^(1A)—, —S(O)— and —S(O)₂—; each of R^(X), R^(Y), R^(Z), and R^(1A) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; or R^(X), R^(Y), R^(Z), or R^(1A) together with R^(D) or R^(E) and the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclic ring; each of R^(D) and R^(E) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl; or R^(D) and R^(E) together with the carbon to which they are attached form a substituted or unsubstituted C₃-C₆ cycloalkyl, or a substituted or unsubstituted 5- to 10-membered heterocyclic; each of R^(F), R^(G) and R^(H) is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl; substituted or unsubstituted heterocyclyl, substituted or unsubstituted —C₆-C₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted —CH₂-C₆-C₁₀ aryl and substituted or unsubstituted —CH₂-5- to 10-membered heteroaryl; or, two or three of R^(F), R^(G) and R^(H) together with the P⁺ to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring having zero, one, or more heteroatoms in addition to the P⁺; or two or three of R^(D), R^(E), R^(F), R^(G) and R^(H) together with the P⁺ form an optionally substituted 5- to 10-membered heterocyclic ring having, zero, one or more heteroatoms in addition to the P⁺.
 2. The compound of claim 1, wherein Y⁻ is bromide, chloride, or iodide.
 3. The compound of claim 1, wherein X¹ is —NHC(O)—.
 4. The compound of claim 1, wherein each of R^(A) and R^(B) are methyl, and R^(C) is selected from the group consisting of hydrogen, methyl, halogen, nitrile, methoxy, and ethoxy.
 5. The compound of claim 1, wherein each of R^(A) and R^(B) are methyl and R^(C) is hydrogen.
 6. The compound of claim 1, wherein each of R^(D) and R^(E) is independently selected from hydrogen, D, substituted or unsubstituted alkyl; or R^(D) and R^(E) together form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted heterocyclic.
 7. The compound of claim 6, wherein R^(D) and R^(E) are both hydrogen.
 8. The compound of claim 6, wherein R^(D) is hydrogen and R^(E) is a C₁-C₄alkyl.
 9. The compound of claim 8, wherein R^(D) is hydrogen and R^(E) is methyl, ethyl, n-propyl, or n-butyl.
 10. The compound of claim 6, wherein R^(D) and R^(E) are taken together with the carbon to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl.
 11. The compound of claim 1, wherein each of R^(F), R^(G) and R^(H) is the same or different and is selected from a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl.
 12. The compound of claim 11, wherein each of R^(F), R^(G) and R^(H) is the same.
 13. The compound of claim 1, wherein R^(F) and R^(G) are the same or different and are each independently a substituted or unsubstituted alkyl, and R^(H) is an aralkyl, or a heteroaralkyl.
 14. The compound of claim 1, wherein R^(F) and R^(G) are the same or different and are each a substituted or unsubstituted alkyl, and R^(H) is:


15. The compound of claim 1, wherein two of R^(F), R^(G) and R^(H) together with the P⁺ to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring having, zero, one, or more heteroatoms in addition to the P⁺.
 16. The compound of claim 15, wherein R^(F) and R^(G) are taken together with the P⁺ to which they are attached to form a 5-, 6-, or 7-membered heterocyclyl, and R^(H) is an aralkyl or a heteroaralkyl.
 17. The compound of claim 15, wherein R^(F) and R^(G) together with the P⁺ to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring having zero, one, or more heteroatoms in addition to the P⁺, and R^(H) is —CH₂—Z; wherein Z is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.
 18. The compound of claim 17, wherein Z is selected from the group consisting of unsubstituted phenyl, phenyl substituted by a C₁-C₄ alkyl, halogen, methoxy, ethoxy, and cyano.
 19. The compound of claim 15, wherein R^(F) and R^(G) together with the P⁺ to which they are attached form a five, six, or seven-membered phosphorus-containing heterocyclic ring.
 20. The compound of claim 1, wherein the compound is selected from those in the Tables below: Compound # STRUCTURE 1

2

3

4

5

6

7

8

9

10

Compound # STRUCTURE 1A

2A

3A

4A

5A

6A

7A

8A

9A

10A


21. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
 22. The composition of claim 21, wherein said composition is formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration.
 23. A method for treating pain, cough, itch, or a neurogenic inflammatory disorder in a patient, comprising administering to said patient an effective amount of a compound of claim
 1. 24. The method of claim 23, wherein said pain is selected from the group consisting of pain due to back and neck pain, lower back pain, cancer pain, gynecological and labor pain, fibromyalgia, arthritis, rheumatoid arthritis, osteoarthritis, rheumatological pains, orthopedic pains, acute and post herpetic neuralgia and other neuropathic pains (including peripheral neuropathy), sickle cell crises, vulvodynia, peri-anal pain, irritable bowel disease, irritable bowel syndrome, inflammatory bowel disease, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urological pains, dental pain, headaches, trigeminal trophic syndrome, erythromelalgia, abdominal wall pain, chronic abdominal wall pain, allergic rhinitis, muscle pain, rectal pain, Levator ani syndrome, proctalgia fugax, hemorrhoid pain, stomach pain, skin ulcers, stomach ulcers, burn pain, ophthalmic irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, dry eye syndrome (chronic ocular pain), complex regional pain syndrome, post-surgical ocular pain, postoperative pain, acute postoperative pain, and procedural pain (i.e., pain associated with injections, draining an abscess, surgery, dental procedures, ophthalmic procedures, ophthalmic irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, arthroscopies and use of other medical instrumentation, cosmetic surgical procedures, dermatological procedures, setting fractures, biopsies, and the like).
 25. The method of claim 23, wherein said cough is selected from the group consisting of cough in patients with asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post viral cough, post-infection cough, chronic idiopathic cough and lung cancer.
 26. The method of claim 23, wherein said itch is selected from the group consisting of itch due to pruritus, brachioradial pruritus, chronic idiopathic pruritus, genital/anal pruritus, notalgia paresthetica, scalp pruritus, allergic dermatitis, contact dermatitis, atopic dermatitis, hand eczema, poison ivy, infections, parasites, insect bites, pregnancy, metabolic disorders, liver or renal failure, drug reactions, allergic reactions, eczema, genital and anal itch, hemorrhoid itch, and cancer.
 27. The method of claim 23, wherein said neurogenic inflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, rosacea, sunburn, pancreatitis, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, chemical warfare agents, and atopic dermatitis.
 28. The method of claim 23, wherein a compound represented by Formula (I) is used in combination with one or more exogenous large pore receptor agonists. 